JP2014514259A - Compounds and methods for the treatment of pain and other disorders - Google Patents

Abstract

The present invention relates generally to pharmaceuticals, particularly metalloprotease inhibitor compounds. More particularly, the present invention provides a novel two-fold display of efficacy, increased metabolic stability, and / or decreased toxicity for currently known MMP-2 and MMP-9 inhibitors for the treatment of pain and other diseases. Provided are a class of compound MMP-2 and MMP-9 inhibitor compounds. Furthermore, the present invention relates to a method for treating pain, addiction and / or withdrawal symptoms in a patient comprising administering to the patient a pain reducing effective amount of a compound of the present invention.

Description

FIELD OF THE INVENTION The present invention generally relates to metalloprotease inhibitory compounds, and more particularly to the treatment of MMP-2 inhibitory compounds and / or MMP-9 inhibitory compounds and pain, substance addiction and withdrawal, and other diseases. Regarding its use.

BACKGROUND OF THE INVENTION Inflammation is defined as a complex biological response of vascular tissue to harmful stimuli (such as pathogens, damaged cells, or irritants). This is a protective attempt by the organism to remove the damaging stimulus and initiate the tissue healing process. Inflammation can be acute (early response) or chronic (occurs over a long period of time). Acute inflammation involves multinucleated leukocytes, while chronic inflammation involves monocytes, macrophages, lymphocytes, and plasma cells (collectively, mononuclear leukocytes). One effect of both acute and chronic inflammation is pain sensation, which can be either neuropathic or nociceptive. Some common illnesses associated with neuropathic pain are low back pain, neuralgia / fibromyalgia, diabetic neuropathic pain, and pain associated with multiple sclerosis. Common illnesses associated with nociceptive pain are joint pain (especially osteoarthritis and rheumatoid arthritis), postoperative pain, cancer-related pain, and HIV-related pain.

  In 1997, a study group by Sommer et al. (Non-Patent Document 1) found that a supra-neural injection of a potent matrix metalloproteinase inhibitor (TAPI-0) in a chronic strangulation injury (CCI) mouse model is the third day of daily injection. Later it was shown that both mechanical allodynia and thermal hyperalgesia can be blocked. At that time, the authors concluded that inhibition of TNF-α was the mechanism of action because the inhibitor (TAPI-0) was a known inhibitor of TNF-α (IC 50 approximately 100 nM). However, it has since been shown that the IC50 for TABI-0 to MMP-9 is 0.5 nM.

  Ji et al. (2) reported that matrix metalloproteinase-9 (MMP-9) was damaged in the early stages of the L5 spinal nerve ligation (SNL) neuropathic pain model in the dorsal root ganglion (DRG) primary. Upregulated in sensory neurons (decreased after day 1 and then after day 3), matrix metalloproteinase-2 (MMP-2) response was delayed in this model (upregulation was initiated from day 7 and day 21 Recently found that it still exists in the eye). Ji et al. Also found that MMP-2 induces neuropathic pain through IL-1β cleavage and astrocytic extracellular signal-regulated kinase (ERK) activation. Ji et al. Also found that endogenous matrix metalloproteinase inhibitors (TIMP-1 and TIMP-2) also inhibit neuropathic pain in this model. Kobayashi et al. (Non-patent document 3) recently found that MMP degrades peripheral myelin basic protein (MBP) and that a broad spectrum hydroxamic acid-containing MMP inhibitor (GM6001) reduces mechanical pain. certified. There are other studies using knockout mice by other groups that have demonstrated the importance of MMP-2 in the induction of chronic neuropathic pain (Non-Patent Document 4, Non-Patent Document 5).

  It has been proposed that drug addiction is the result of drug-induced learning and long-term memory formation. By using each drug, the memory of the drug can be reactivated and integrated to maintain the original memory (Non-patent Document 6). Endogenous proteins that have been found to play an important role in synaptic plasticity are matrix metalloproteases (MMP), in particular MMP-2 and MMP-9. MMP-2 and MMP-9 have been found to be involved in axon extension, receptor axon guidance, axon myelination, and clarification of pathways through the extracellular matrix (Non-Patent Document 7). MMP-2 and MMP-9 have also been found to be closely involved in behavioral sensitization and reward induced by methamphetamine (Non-patent Document 8) and cocaine (Non-patent Document 9). For example, Nabeshma et al. (Non-Patent Document 10) show that methamphetamine-inducible when MMP-2 / -9 inhibitor is injected into either the right ventricle or frontal cortex of rats (by a mini-osmotic pump). We found that behavioral sensitization and conditioned place preference were blocked and dopamine release into the nucleus accumbens was reduced.

  Both chronic tolerance and hyperalgesia frequently occur among chronic opioid users. Tolerance is an indication that induces changes in exposure to opioids that reduce the pain-blocking effect of the drug over time. The result of tolerance is that the user needs a higher dosage of opioid to maintain a therapeutic effect. Hyperalgesia is a condition in which a user becomes hypersensitive to exposure to opioid exposure. Patients who use opioids (such as morphine) chronically become more sensitive to the original pain, and in many cases, new pain types have been reported for the opioid itself. Both tolerance and hyperalgesia are factors that help explain the prevalence of opioids for addiction among chronic users. Recently, Song et al. (The Journal of Neuroscience, 30 (22), (2010), 7613-7623) found a strong association between physical dependence due to opioid withdrawal and increased MMP-9 activity in the dorsal horn. It was. These researchers found that administration of exogenous MMP-9 into the spine can induce both morphine-like withdrawal behavior and mechanical allodynia in normal mice. Withdrawal behavior when MMP-9 inhibitor (2- [benzyl- (4-methoxy-benzenesulfonyl) -amino] -5-diethylamino-N-hydroxy-3-methyl-benzamide) was injected intrathecally into morphine withdrawal mice Can be eliminated. Co-administration of either an MMP-2 inhibitor or an MMP-9 inhibitor can significantly reduce mouse morphine tolerance. The compounds used in all the above studies to block either MMP-2 and / or MMP-9 activity were hydroxamic acid-containing MMP inhibitors with known toxic side effects.

  Matrix metalloproteinases (MMPs) are a family of structurally related zinc-containing enzymes that have been reported to mediate connective tissue destruction in normal physiological processes such as embryonic development, regeneration, and tissue remodeling . Overexpression of MMPs or imbalances between MMPs has been proposed as a factor in inflammatory, malignant and degenerative disease processes characterized by extracellular matrix or connective tissue destruction. Thus, MMPs are associated with several inflammatory, malignant and degenerative diseases (rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epithelial and gastric ulcers, atherosclerotic arteries) It is a target for therapeutic inhibitors in sclerosis, neointimal proliferation (which causes restenosis and ischemic heart failure), and tumor metastasis without pain). MMP-2 (72 kDa gelatinase / gelatinase A) and MMP-9 (92 kDa gelatinase / gelatinase B) degrade the extracellular substrate components of the basement membrane. Its substrates include type IV and type V collagen, fibronectin, elastin, and denatured stromal collagen. Substrate degradation attributed to this proteinase has been shown to play an important role in the progression of diseases such as atherosclerosis, inflammation, stroke, and tumor growth and metastasis. However, until recently, there has been little published scientific literature regarding the use of MMP-2 inhibitors and / or MMP-9 inhibitors to treat pain and / or addiction.

  Matrix metalloproteinases have been clinically tested in a few indications (mostly arthritis and cancer). In particular, inhibitors that have entered clinical trials for oncological indications include purinomastert (AG3340; Agouron / Pfizer), BAY 12-9656 (Bayer Corp.), batimistat (BB-94; British Biotech, Ltd., ), BMS-275291 (former name D2163; Celltech / Bristol-Myers Squibb), Malimastert (BB 2516; British Biotech, Ltd./Schering-Plough), MMI270 (B) (former name CGSv270tANo; , And Metastat (COL-3; CollaGenex). Many of the hydroxamic acids, including inhibitors, are very toxic to humans. For example, marimastat containing a hydroxamate moiety showed time-dependent and dose-dependent musculoskeletal toxicity (arthralgia, myalgia, tendonitis) in humans. Other toxicities of marimastat include ascites, disseminated cancer, chills, cholangitis, dizziness, dyspnea, edema, fatigue, fever, gastrointestinal tract (anorexia, nausea, vomiting, diarrhea, constipation), gastrointestinal bleeding, Includes headache, heartburn, hepatotoxicity, hypercalcemia, hyperglycemia, rash, and shortness of breath. It is not known whether the toxicity exhibited by many MMP inhibitors is attributable to the hydroxamic acid moiety contained in many of these broad spectrum MMP inhibitors, but some by having MMP inhibitors that do not contain a hydroxamic acid group It is clear that the potential metabolic tendency of can be reduced.

  Kusner et al. (Non-Patent Document 11) showed an example of how metabolically induced conversion levels (especially those mediated by cytochrome P450) can often be reduced by the incorporation of deuterium into the drug. This rate of decrease in cytochrome P450-induced metabolism can sometimes be translated directly into enhanced bioavailability. The reason for this is that elemental substitution of hydrogen by deuterium in the drug changes the strength of the drug's carbon-deuterium bond while maintaining a three-dimensional surface very similar to that of the non-deuterated version. Due to the fact that. Replacement of hydrogen with deuterium can produce isotope effects that can alter the pharmacokinetics of the drug. In reactions where the rate of C—H bond cleavage is rate limiting, the same reaction of the CD analog is reduced. For example, Schneider et al. (12) described one aromatic ring of the COX-2 inhibitor Rofecoxib (4- (4-methylsulfonylphenyl) -3-phenyl-5H-furan-2-one). Replacement of several surrounding hydrogen atoms with deuterium (positions 2 ', 3', 4 ', 5', and 6 ') does not affect the oral biological properties of the drug without affecting its COX-2 selectivity It has been shown to increase availability. When this strategy is applied to the tryptophan-based acid S-3304, it reduces its vulnerability to cytochrome P-450 hydrogenation and ultimately enhances its overall bioavailability and possibly its target Tissue compound concentrations can be increased.

  Another possible incorporation effect of deuterium into a drug is an effect on its polymorphic (ie, different crystalline form) properties. For example, Hirota and Urushibara (Non-Patent Document 13) show that the replacement of one vinyl group on arocinnamic acid with hydrogen to deuterium can change both the melting point of the molecule and the intensity of the X-ray diffraction pattern. Indicated. Lin and Guillory (14) have shown that sulfanilamide-d4 has a low heat of transition and heat of fusion in its various crystalline states compared to its corresponding non-deuterated form. Finally, Crawford et al. (Non-Patent Document 15) take a unique configuration in which the crystal form of fully deuterated pyridine can only be obtained using a non-deuterated parent substance under high pressure. Recently shown. The study clearly showed that the substitution of hydrogen with deuterium changed the strength of the interaction between the various atoms in adjacent molecules, changing the crystal configuration to a more energetically favorable crystal configuration. This change in crystal configuration or polymorphism can improve solubility and improve bioavailability.

  Sucholeiki (US Pat. No. 6,057,059) showed that the partial deuteration of a matrix metalloproteinase (MMP) inhibitor can improve the bioavailability of this inhibitor compared to its non-deuterated parent substance. In human blood, MMP inhibitor S3304 was known to form several hydroxylated metabolites (Non-patent Document 16). Two of the major metabolites were involved in the hydroxylation around the indole ring of the tryptophan moiety of the S3304 molecule and the third was involved in the hydroxylation of the toluenemethyl moiety of the S3304 molecule. When the terminal toluenemethyl moiety of S3304 is deuterated, the compound is in vivo for mechanical allodynia in a spinal nerve ligation (SNL) mouse model compared to vehicle control and non-deuterated parent (S3304). Higher biological activity was observed.

  There are a small number of non-hydroxamic acid-containing MMP inhibitors reported in the literature, and even fewer of these are in clinical trials in cancer and / or inflammation. However, they have not been tested for pain, drug addiction and do not reduce tolerance and withdrawal associated with opioid use in animal models or humans. A series of MMP-2 inhibitory compounds and / or MMP-9 inhibitory compounds are presented and their methods of use in the inhibition of pain and other disorders are disclosed.

International Publication No. 2010/075287

Somer C, Schmidt C, George A, Toyka KV. Neurosci Lett. 1997; 237: 45-48. Nature Medicine 14 (13), (2008), 331-336 Molecular and Cellular Neuroscience, 39, (2008), 619-627. Komori K.K. Et al., FEBS Lett. 557: 125-128 (2004). Folguera, A .; PNAS, 106 (38), 16451-16456 (2009). Hyman, S .; E. Malenka, R .; C. Nestler, E .; J. et al. Neural mechanisms of addition: the role of rewarded-related learning and memory, Annu. Rev. Neurosci. , 29, 565-598, (2006) Wright, J .; W. Harding, J .; W. Contributions of matrix metalloproteinases to neural plasticity, habitation, associative learning and drug addition, Natural Plasticity, Vol. 2009, 12 pages, (2009) Mizoguchi, H .; Yamada, K .; Niwa, M .; Mouri, A .; Mizuno, T .; Noda, Y .; Nitta, A .; Itohaira, S .; Banno, Y .; and Nabeshima, T .; Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and -9 defensive rice, J .; Neurochem, 100, 1579-1588, (2007) Brown, T.W. E. Forquer, M .; R. Cocking, D .; L. Jansen, H .; T.A. Harding, J .; W. and Sorg, B .; A. Role of matrix metalloproteinases in the acquisition and resorsionation of cocaine-induced conditioned preference, Learning and Memory 23, 214 (214); Mizoguchi, H .; Yamada, K .; Niwa, M .; Mouri, A .; Mizuno, T .; Noda, Y .; Nitta, A .; Itohaira, S .; Banno, Y .; and Nabeshima, T .; ; Role of matrix metalloproteinase and tissue inhibitor of MMP in methamphetamine-induced behavioral sensitization and reward: implications for dopamine receptor down-regulation and dopamine release, Journal of Neurochemistry, 102,1548-1560, (2007) Kushner, D.C. J. et al. Baker, A .; Dunstal, T .; G. Can J. Physiol Pharmacol, 77 (2), (1999) p. 79-88 Scheneider, F.M. Et al. BiRDS Pharma GmbH, Arzneimtel Forschung (2006), 56 (4), p. 295-300 Bulletin of the Chemical Society of Japan, 32 (7), (1959), 703-706. Journal of Pharmaceutical Science, Vol. 59 (7), (2006), 972-979 Crawford, S.M. Et al., Angelwande Chemie International Edition, 48 (4), (2009), 755-757. Chiappori, A .; A. Et al., Clin. Cancer Res. 2007, 13 (7), 2091-2099

The present invention relates to compounds and pharmaceutical compositions for use as medicaments for the treatment of MMP-mediated conditions or diseases.

  One embodiment of the present invention is a novel method for treating pain, drug addiction and / or reducing tolerance and withdrawal side effects due to substance abuse utilizing MMP-2 inhibitors and / or MMP-9 inhibitors Regarding the method.

  MMP-2 inhibitors and / or MMP-9 inhibitors may be represented by the general formulas (I-XIII):

（式中、
前述の式（Ｉ〜ＸＩＩＩ）中の全変数は、本明細書中の以下に定義の通りである）、そのＮ−オキシド、重水素化アナログ、薬学的に許容され得る塩、プロドラッグ、処方物、多形、互変異性体、ラセミ混合物、または立体異性体によって示す。

(Where
All variables in the aforementioned formulas (I-XIII) are as defined herein below), their N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations Product, polymorph, tautomer, racemic mixture, or stereoisomer.

R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Are optionally substituted one or more times.

  The MMP-2 inhibitory compound and / or MMP-9 inhibitory compound of the present invention may be combined with other metalloprotease-mediated diseases (rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis). Disease, chronic obstructive pulmonary disease, eye disease, neurological disease, psychiatric disease, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, retinal vascular disease, addiction Age, dementia, cardiomyopathy, renal tubular disorder, diabetes, psychosis, dyskinesia, pigmentation, hearing loss, inflammatory and fibrotic syndrome, intestinal bowel syndrome, allergy, Alzheimer's disease, Arterial plaque formation, periodontal disease, viral infection, stroke, cardiovascular disease, reperfusion injury, trauma, chemical exposure to tissues or oxidative damage , Wound healing, hemorrhoids, skin beautifying, and pain etc.).

  In particular, the MMP-2 inhibitory compound and / or MMP-9 inhibitory compound of the present invention can be used in the treatment of pain, drug addiction and / or withdrawal side effects due to substance abuse in patients, and the method is effective. Administering to a patient an amount of a compound of the invention in combination with a carrier, wherein the patient has increased or worsened sensitivity to pain (such as hyperalgesia, causalgia, and allodynia); acute pain; burn pain; non- Typical facial pain; neuropathic pain; back pain; complex local pain syndrome type I and II; joint pain; sports injury pain; pain associated with viral infection (eg, HIV, post-polio syndrome, and postherpetic neuralgia) Phantom limb pain; labor pains; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; physiological pain; inflammatory pain; Na, irritable bowel syndrome (IBS), and inflammatory bowel disease); neuropathic pain; neuralgia; painful diabetic neuropathy; traumatic nerve injury; spinal cord injury; drug addiction and / or opioids or other addiction drugs Suffers from resistance to or withdrawal from.

  The present invention also provides MMP-2, MMP-9 and / or useful as an active ingredient in a pharmaceutical composition for the treatment or prevention of metalloprotease (particularly MMP-2 and / or MMP-9) mediated diseases. Other metalloprotease inhibitory compounds are provided. The present invention also includes such compounds in pharmaceutical compositions for oral or parenteral administration, including one or more MMP-2 inhibitory compounds and / or MMP-9 inhibitory compounds disclosed herein. Intended for use.

  The present invention further provides heterobiology according to standard methods known in the clinic for the treatment of diseases or conditions arising from or related to metalloproteases (particularly MMP-2), including prophylactic and therapeutic treatments. Formulations containing cyclic metalloprotease inhibitor compounds (oral, rectal, topical, intrathecal, intravenous, parenteral (including but not limited to intramuscular and intravenous), ocular (eye ( administration), transdermal, inhalation (including but not limited to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous, or intraarticular formulations. To inhibit MMP-2, MMP-9 and / or other metalloproteases. Nevertheless, the most suitable route in any given case depends on the nature and severity of the condition being treated and the nature of the active ingredient. The compounds derived from the present invention conveniently exist in unit dosage forms and are prepared by any method well known in the pharmaceutical art.

  The MMP-2 inhibitory compound and / or MMP-9 inhibitory compound of the present invention may be used as a disease-modifying antirheumatic drug, non-steroidal anti-inflammatory drug, COX-2 selective inhibitor, COX-1 inhibitor, immunosuppressive drug, steroid, It can be used in combination with biological response modifiers or other anti-inflammatory agents.

FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)). FIG. 1 (AJ) is a graph showing that intrathecal administration of Compound 10 significantly attenuates behavioral signs of naloxone-induced morphine withdrawal compared to control and vehicle in CD-1 mice (n = 5 mice (control); n = 13 mice (DMSO vehicle control), and n = 14 mice (compound 10 administration)).

DETAILED DESCRIPTION OF THE INVENTION The term “D” when used herein alone or as part of a chemical structure or group refers to deuterium.

  The term “deuterium” when used herein alone or as part of another group refers to a stable isotope of hydrogen having a mass number of 2.

  The term “deuteration” when used herein alone or as part of a group refers to an optionally substituted deuterium atom.

  The term “deuterated analog” as used herein alone or as part of a group, optionally substituted deuterium atoms at selected positions in and around the molecule. Indicates.

The term “alkyl” or “alk” as used herein alone or as part of another group preferably has 1 to 10 carbons in the straight chain, most preferably lower alkyl. And optionally substituted linear and branched saturated hydrocarbon groups having groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like are included. Exemplary substituents can include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (eg, to form a benzyl group), cycloalkyl , Cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH ₂ —CO—), substituted carbamoyl ((R ¹⁰ ) (R ¹¹ ) N—CO— (Wherein R ¹⁰ or R ¹¹ is as defined below, except that at least one R ¹⁰ or R ¹¹ is not hydrogen)), amino, heterocyclo, monoalkylamino, dialkylamino, or thiol (-SH).

The term “heteroalkyl” which can be used interchangeably with the term “alkyl” is preferably an optionally substituted straight chain having 1 to 10 carbons, most preferably a lower alkyl group, in the straight chain. And a branched saturated hydrocarbon group. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like are included. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (eg, to form a benzyl group), cycloalkyl , Cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH ₂ —CO—).

  The term “lower alk” or “lower alkyl” as used herein refers to such optionally substituted groups as described above for alkyls having 1 to 4 carbon atoms in the straight chain. .

  The term “alkoxy” refers to an alkyl group as described above attached through an oxygen bond (—O—).

The term “alkenyl” as used herein alone or as part of another group contains at least one carbon-carbon double bond in the chain, preferably 2-10 in the straight chain. Optionally substituted linear and branched hydrocarbon groups having the following carbons: Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH ₂ —CO—), substituted carbamoyl.

The term “alkynyl” when used herein alone or as part of another group contains at least one carbon-carbon triple bond in the chain, preferably 2-10 in the straight chain. Figure 8 shows optionally substituted linear and branched hydrocarbon groups having carbon. Exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, noninyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH ₂ —CO—), substituted carbamoyl.

  The term “cycloalkyl”, when used herein alone or as part of another group, optionally contains from 1 to 3 rings and optionally from 3 to 9 carbons per ring. Represents a substituted saturated cyclic hydrocarbon ring system (including a bridged ring system). Exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include, but are not limited to, one or more of the above alkyl groups or one or more of the above groups as alkyl substituents.

  The term “ar” or “aryl” when used herein alone or as part of another group preferably comprises 1 or 2 rings and 6 to 12 ring carbons. An optionally substituted homocyclic aromatic group is shown. Exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more nitro groups, the above alkyl groups, or the above groups as alkyl substituents.

  The term “heterocycle” or “heterocyclic system” refers to a heterocyclyl group, heterocyclenyl group as described herein comprising carbon atoms and 1 to 4 heteroatoms independently selected from N, O, and S. Or a heteroaryl group (including any bicyclic or tricyclic group in which any of the above defined heterocycles is fused to one or more heterocyclic, aryl, or cycloalkyl groups). Nitrogen and sulfur heteroatoms can optionally be oxidized. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocycles described herein can be substituted on a carbon atom or a nitrogen atom.

  Examples of heterocycles include 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- Quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzoimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzo Tetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1 , 5,2 Dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochrominyl, isoindolinyl, isoindolinyl Isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4 -Oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, oxindolyl (oxin dolyl), phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidinyl, piperidinyl, piperidyl , Pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl, quinuclidinyl , Tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H 1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantenyl, thiazolyl, thienyl, thienothiazolyl, thienooxa Zolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, It is not limited.

  “Heterocyclenyl” is a heteroelement in which one or more carbon atoms in the ring system is other than carbon (eg, a nitrogen, oxygen, or sulfur atom) and at least one carbon-carbon double bond or carbon-nitrogen. It represents a non-aromatic monocyclic or polycyclic hydrocarbon ring system of about 3 to about 10 atoms, preferably about 4 to about 8 atoms, including double bonds. The ring size of the ring system can contain 5 to 6 ring atoms. The designation aza, oxa or thia as a prefix before heterocyclenyl defines that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A heterocyclenyl can be optionally substituted with one or more substituents as defined herein. The nitrogen or sulfur atom of the heterocyclenyl can also be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide. “Heterocyclenyl” as used herein includes, as an example, Paquette, Leo A. et al. “Principles of Modern Heterocyclic Chemistry” (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic” John Wiley & Sons, New York, 1950-present), in particular, 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc.", 82: 5566 (1960) (in its entirety) Heterocyclenyl described in (incorporated herein by reference), but is not limited thereto. Exemplary monocyclic azaheterocyclenyl groups include 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine. , 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. An exemplary polycyclic oxaheterocyclenyl group is 7-oxabicyclo [2.2.1] heptenyl.

  “Heterocyclyl” or “heterocycloalkyl” refers to about 3 to about 10 carbon atoms, desirably one or more carbon atoms in the ring system is a heteroelement other than carbon (eg, nitrogen, oxygen, or sulfur), desirably Denotes a non-aromatic saturated monocyclic or polycyclic ring system of 4 to 8 carbon atoms. The ring size of the ring system can contain 5 to 6 ring atoms. The designation aza, oxa or thia as a prefix before heterocyclyl defines that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted with one or more substituents as defined herein which may be the same or different. The nitrogen or sulfur atom of the heterocyclyl can also be optionally oxidized to the corresponding N-oxide, S-oxide, or S, S-dioxide.

  “Heterocyclyl” as used herein includes, as an example, Paquette, Leo A. et al. "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclomonic." John Wiley & Sons, New York, 1950-present), in particular, 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc.", 82: 5566 (1960) Including, but not limited to. Exemplary monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiopyranyl, and the like However, it is not limited to these.

  “Heteroaryl” is an aromatic monocyclic or multicyclic ring of about 5 to about 10 atoms in which one or more atoms in the ring system is a heteroelement other than carbon (eg, nitrogen, oxygen, or sulfur) Indicates a ring system. The ring size of the ring system contains 5 to 6 ring atoms. “Heteroaryl” may be substituted by one or more substituents as defined herein which may be the same or different. The designation aza, oxa or thia as a prefix before heteroaryl defines that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen atom of the heteroaryl can be optionally oxidized to the corresponding N-oxide. Heteroaryl includes, as used herein, by way of example Paquette, Leo A. et al. "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclomonic." John Wiley & Sons, New York, 1950-present), in particular, 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc.", 82: 5566 (1960) Is included, but is not limited thereto. Exemplary heteroaryl and substituted heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a] pyridine , Imidazo [2,1-b] thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl, 1 , 3,5-triazinyl, benzothiazolyl, dioxolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl Oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl, 1,3,4-thiadiazolyl, 1, 2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl, 5-thioxo-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl, These include, but are not limited to, triazolyl and triazolonyl.

The term “amino” refers to the radical —NH ₂ where one or both of the hydrogen atoms can be replaced with an optionally substituted hydrocarbon group. Exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino, and ethyldimethylamino.

  The term “cycloalkylalkyl” refers to a cycloalkyl-alkyl group in which the above cycloalkyl is attached through an alkyl as defined above. A cycloalkylalkyl group can contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.

  The term “arylalkyl” refers to an aryl group as described above attached through an alkyl as defined above.

  The term “heteroarylalkyl” denotes a heteroaryl group as defined above attached through an alkyl as defined above.

  The term “heterocyclylalkyl” or “heterocycloalkylalkyl” refers to a heterocyclyl group as defined above attached through an alkyl as defined above.

  The terms “halogen”, “halo”, or “hal” when used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.

  The term “haloalkyl” refers to a halo group as defined above attached through an alkyl as defined above. Fluoroalkyl is an exemplary group.

  The term “aminoalkyl” refers to an amino group as defined above attached through an alkyl as defined above.

  The phrase “bicyclic fused ring system in which at least one ring is partially saturated” refers to an 8 to 13 membered fused bicyclic ring group in which at least one ring is non-aromatic. The ring group has 1 to 4 heteroatoms selected independently from carbon atoms and optionally N, O, and S. Examples include but are not limited to indanyl, tetrahydronaphthyl, tetrahydroquinolyl, and benzocycloheptyl.

  The phrase “a tricyclic fused ring system in which at least one ring is partially saturated” refers to a 9-18 membered fused tricyclic ring group in which at least one ring is non-aromatic. The ring group has 1 to 7 heteroatoms, independently selected from carbon atoms and optionally N, O, and S. Examples include, but are not limited to, fluorene, 10,11-dihydro-5H-dibenzo [a, d] cycloheptene, and 2,2a, 7,7a-tetrahydro-1H-cyclobuta [a] indene.

  The term “isotope enrichment” changes the relative abundance of a given element's isotope, resulting in the enrichment of one particular isotope and the depletion of another isotope. A process.

  The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds in which the parent compound has been modified by the production of its acid or basic salts. Examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic residues (such as amines) and alkali or organic salts of acidic residues (such as carboxylic acids). It is not limited to. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts and organic acids derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid. (Acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid , 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid, and the like.

  The term “polymorph” refers to a chemical form of a particular crystal configuration. Certain polymorphs may exhibit high thermodynamic stability and may be more suitable for inclusion in pharmaceutical formulations than other polymorphic forms. Compounds having hydrogen replaced with deuterium can form polymorphs that can enhance their solubility and / or bioavailability.

  The term “deuterated analog”, when used herein alone or as part of a group, refers to an optionally substituted deuterium atom instead of hydrogen.

  Kusner et al. (Kushner, D.J .; Baker, A .; Dunstal, TG Can J. Physiol Pharmacol, 77 (2), (1999) p. 79-88) incorporated deuterium into drugs. An example of how metabolism-induced conversion levels (especially conversion levels mediated by cytochrome P450) can often be reduced. This rate of decrease of cytochrome P450-induced metabolism can sometimes be directly translated into enhanced bioavailability. The reason for this is due to the fact that atomic substitution of hydrogen by deuterium in the drug changes the strength of the drug's carbon-deuterium bond while maintaining the same three-dimensional surface as the non-deuterated version. Replacement of hydrogen with deuterium can produce isotope effects that can alter the pharmacokinetics of the drug. In reactions where the rate of C—H bond cleavage is rate limiting, the same reaction of the CD analog is reduced. For example, Schneider et al. (Scheneider, F. et al., BiRDS Pharma GmbH, Arzneimtel Forschung (2006), 56 (4), p. 295-300) is a recoxib (4- (4-methylsulfonylphenyl) COX-2 inhibitor. ) -3-Phenyl-5H-furan-2-one) with replacement of several hydrogen atoms around one aromatic ring with deuterium (2 ′, 3 ′, 4 ′, 5 ′ and 6 ′ positions) Have been shown to enhance the oral bioavailability of drugs without affecting their COX-2 selectivity.

  The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reaction of the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or mixture of the two. . Organic solvents include, but are not limited to, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed. Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is incorporated herein by reference.

  The phrase “pharmaceutically acceptable” refers to excessive toxicity, irritation, allergic reactions, or other problems or complications that are within sound medical judgment and that are commensurate with a reasonable benefit / risk ratio. Compounds, materials, compositions, and / or dosage forms suitable for use in contact with human and animal tissue without disease are shown.

  The term “N-oxide” includes a nitrogen atom (such as in a pyridyl group) at about −10 to 80 ° C. (desirably about 0 ° C.) in an inert solvent (such as dichloromethane) in a known manner. And a compound obtainable by reaction of hydrogen peroxide or peracid (such as 3-chloroperoxybenzoic acid).

  “Substitution” does not exceed the normal valence of the indicated atom, and if substitution results in a stable compound, one or more hydrogens on the atom indicated in the expression using “substitution” may be substituted with the indicated group. It is intended to indicate that it is replaced with a group selected from When the substituent is a keto (ie, ═O) group, two hydrogens on the atom are replaced.

Unless the moiety of the compound of the present invention is defined as unsubstituted, the moiety of the compound can be substituted. In addition to the optional substituents provided above, the moieties of the compounds of the present invention can be optionally substituted with one or more groups selected independently from the following.
C ₁ -C ₄ alkyl;
C ₂ -C ₄ alkenyl;
C ₂ -C ₄ alkynyl;
CF ₃ ;
Halo;
OH;
O- _(C 1 ~C ₄ alkyl);
OCH ₂ F;
OCHF ₂ ;
OCF ₃ ;
_{OC (O) - (C 1} ~C 4 alkyl);
_{OC (O) - (C 1} ~C 4 alkyl);
_{OC (O) NH- (C 1} ~C 4 alkyl);
_{OC (O) N (C 1} ~C 4 _alkyl) 2;
OC (S) NH— (C ₁ -C ₄ alkyl);
_{OC (S) N (C 1} ~C 4 _alkyl) 2;
SH;
S- (C ₁ -C ₄ alkyl);
_{S (O) - (C 1} ~C 4 alkyl);
_{S (O) 2 - (C} 1 ~C 4 alkyl);
_{SC (O) - (C 1} ~C 4 alkyl);
_{SC (O) O- (C 1} ~C 4 alkyl);
NH ₂ ;
_{N (H) - (C 1} ~C 4 alkyl);
N _(C 1 ~C _{4 alkyl)} 2;
N (H) C (O) - (C 1 ~C 4 alkyl);
_{N (CH 3) C (O} ) - (C 1 ~C 4 alkyl);
N (H) C (O) -CF 3;
_{N (CH 3) C (O} ) -CF 3;
N (H) C (S) - (C 1 ~C 4 alkyl);
_{N (CH 3) C (S} ) - (C 1 ~C 4 alkyl);
_{N (H) S (O)} 2 - (C 1 ~C 4 alkyl);
N (H) C (O) NH ₂ ;
N (H) C (O) NH- (C 1 ~C 4 alkyl);
_{N (CH 3) C (O} ) NH- (C 1 ~C 4 alkyl);
N (H) C (O) N (C 1 ~C 4 _alkyl) 2;
_{N (CH 3) C (O} ) N (C 1 ~C 4 _alkyl) 2;
N (H) S (O) ₂ NH ₂ );
_{N (H) S (O)} 2 NH- (C 1 ~C 4 alkyl);
_{N (CH 3) S (O} ) 2 NH- (C 1 ~C 4 alkyl);
_{N (H) S (O)} 2 N (C 1 ~C 4 _alkyl) 2;
_{N (CH 3) S (O} ) 2 N (C 1 ~C 4 _alkyl) 2;
N (H) C (O) O- (C 1 ~C 4 alkyl);
_{N (CH 3) C (O} ) O- (C 1 ~C 4 alkyl);
_{N (H) S (O)} 2 O- (C 1 ~C 4 alkyl);
_{N (CH 3) S (O} ) 2 O- (C 1 ~C 4 alkyl);
_{N (CH 3) C (S} ) NH- (C 1 ~C 4 alkyl);
_{N (CH 3) C (S} ) N (C 1 ~C 4 _alkyl) 2;
_{N (CH 3) C (S} ) O- (C 1 ~C 4 alkyl);
N (H) C (S) NH ₂ ;
NO ₂ ;
CO ₂ H;
CO ₂ - _(C 1 ~C ₄ alkyl);
C (O) N (H) OH;
C (O) N (CH ₃ ) OH:
C (O) N (CH ₃ ) OH;
_{C (O) N (CH 3} ) O- (C 1 ~C 4 alkyl);
C (O) N (H) - (C 1 ~C 4 alkyl);
_{C (O) N (C 1} ~C 4 _alkyl) 2;
C (S) N (H) - (C 1 ~C 4 alkyl);
_{C (S) N (C 1} ~C 4 _alkyl) 2;
C (NH) N (H) - (C 1 ~C 4 alkyl);
_{C (NH) N (C 1} ~C 4 _alkyl) 2;
_{C (NCH 3) N (H} ) - (C 1 ~C 4 alkyl);
_{C (NCH 3) N (C} 1 ~C 4 _alkyl) 2;
_{C (O) - (C 1} ~C 4 alkyl);
_{C (NH) - (C 1} ~C 4 alkyl);
_{C (NCH 3) - (C} 1 ~C 4 alkyl);
_{C (NOH) - (C 1} ~C 4 alkyl);
_{C (NOCH 3) - (C} 1 ~C 4 alkyl);
CN;
CHO;
CH ₂ OH;
CH ₂ O- _(C 1 ~C ₄ alkyl);
CH ₂ NH ₂ ;
_{CH 2 N (H) - (} C 1 ~C 4 alkyl);
CH ₂ N (C ₁ -C ₄ alkyl) ₂ ;
Aryl;
Heteroaryl;
Cycloalkyl; and heterocyclyl.

  In one embodiment of the invention, the metalloprotease inhibitor compound is of the general formula (I-XIII):

（式中、
前述の式（Ｉ〜ＸＩＩＩ）中の全変数は、本明細書中の以下に定義の通りである）、そのＮ−オキシド、重水素化アナログ、薬学的に許容され得る塩、プロドラッグ、処方物、互変異性体、ラセミ混合物、または立体異性体によって示すことができる。

(Where
All variables in the aforementioned formulas (I-XIII) are as defined herein below), their N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations Product, tautomer, racemic mixture, or stereoisomer.

R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Are optionally substituted one or more times.

  The compounds of the invention represented by the above formula are intended to include all diastereomers and enantiomers, as well as racemic mixtures. Racemic mixtures can be separated by chiral salt resolution or chiral column HPLC chromatography. As noted above, the compounds of the invention represented by the above formula include deuterated analogs in which one or more hydrogens of the molecule are replaced with deuterium atoms.

  More specifically, the compounds of formulas (I-XIII) can be selected from, but not limited to:

本発明はまた、上記の任意の本発明のＭＭＰ−２阻害化合物および／またはＭＭＰ−９阻害化合物を含む薬学的組成物に関する。本発明によれば、本発明のいくつかの実施形態は、有効量の本発明のＭＭＰ−２阻害化合物および／またはＭＭＰ−９阻害化合物および薬学的に許容され得るキャリアを含むことができる薬学的組成物を提供する。

The present invention also relates to pharmaceutical compositions comprising any of the MMP-2 inhibitory compounds and / or MMP-9 inhibitory compounds of the present invention described above. In accordance with the present invention, some embodiments of the present invention include a pharmaceutical that can comprise an effective amount of an MMP-2 and / or MMP-9 inhibitor compound of the present invention and a pharmaceutically acceptable carrier. A composition is provided.

  The invention also relates to methods for inhibiting MMP-2 and / or MMP-9 and methods for treating diseases or conditions mediated by MMP-2 and / or MMP-9 enzymes. Such a method comprises the MMP-2 inhibitory compound and / or MMP-9 inhibitory compound of the invention (compounds of formula (I-XIII) as defined above, deuterated analogs or N-oxides, pharmaceutically acceptable salts thereof) , Polymorphs, or stereoisomers). Examples of diseases or conditions mediated by MMP-2 and / or MMP-9 enzymes include reduced sensitivity to pain (such as hyperalgesia, causalgia, and allodynia); acute pain; burn pain; mechanical -Induced pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome type I and II; arthritic joint pain; sports injury pain; pain associated with viral infections and postherpetic neuralgia Phantom limb pain; labor pains; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; physiological pain; inflammatory pain; acute inflammatory condition / visceral pain, angina, irritable bowel syndrome (IBS), Neuropathic pain; neuralgia; painful diabetic neuropathy; traumatic nerve injury; spinal cord injury; drug addiction and opioid tolerance or opioids or other addiction compounds Including but leaving, without limitation.

  In some embodiments of the invention, an MMP-2 inhibitory compound and / or an MMP-9 inhibitory compound as defined above is used to produce a medicament for the treatment of a disease mediated by MMP-2 and / or MMP-9. Used in.

  In some embodiments, an MMP-2 inhibitory compound as defined above is a drug, agent or therapeutic agent ((a) a disease modifying anti-rheumatic drug; (b) a non-steroidal anti-inflammatory drug; (c) COX − (D) COX-1 inhibitors; (e) immunosuppressive drugs; (f) steroids; (g) biological response modifiers; (h) opioids, or (i) treatment of chemokine-mediated diseases. Such as, but not limited to, other anti-inflammatory or therapeutic agents useful in the present invention.

  Examples of disease modifying anti-rheumatic drugs include, but are not limited to, methotrexate, azathioptrineluflunomide, penicillamine, gold salts, mycophenolate, mofetil, and cyclophosphamide.

  Examples of non-steroidal anti-inflammatory drugs include, but are not limited to, piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.

  Examples of COX-2 selective inhibitors include, but are not limited to, rofecoxib, celecoxib, and valdecoxib.

  Examples of COX-1 inhibitors include but are not limited to piroxicam.

  Examples of immunosuppressive drugs include, but are not limited to, methotrexate, cyclosporine, leflunimide, tacrolimus, rapamycin, and sulfasalazine.

  Examples of steroids include, but are not limited to, p-methazone, prednisone, cortisone, prednisolone, and dexamethasone.

  Examples of biological response modifiers include, but are not limited to, anti-TNF antibodies, TNF-α antagonists, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, and anti-adhesion molecules.

  Examples of anti-inflammatory or therapeutic agents include p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, thalidomide, leukotriene inhibitors, and other small molecule inhibitors of pro-inflammatory cytokine production. It is not limited.

  According to another embodiment of the invention, the pharmaceutical composition comprises an effective amount of a compound of the invention, a pharmaceutically acceptable carrier, and (a) a disease modifying anti-rheumatic drug; (b) non-steroidal. (C) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive drug; (f) a steroid; (g) a biological response modifier; (h) an opioid; or (H) may include a drug, agent, or therapeutic agent selected from other anti-inflammatory or therapeutic agents useful in the treatment of chemokine-mediated diseases.

  The MMP inhibitory activity of the MMP inhibitor compounds of the present invention can be measured using any suitable assay known in the art. A standard in vitro assay for MMP-2 inhibitory activity is described in Example 130, and MMP-9 is described in Example 131. In addition, standard in vitro assays for the measurement of MMP-1, MMP-7, MMP-3, MMP-12, and MMP-13 are described in Examples 132-136. A standard in vitro assay for measuring human and mouse microsome stability is shown in Example 105. The in vivo pain inhibitory properties of the MMP inhibitor compounds of the present invention can be measured using any suitable animal model known in the art. Standard in vivo tests for measuring neuropathic pain inhibition are described in Examples 110 and 111, and tests for measuring inflammatory pain are described in Example 120. Finally, a standard in vivo test for measurement of morphine tolerance and naloxone-induced morphine withdrawal is described in Example 125, and a standard in vivo measurement for cue-initiated relapse. A vivo test is described in Example 126.

The MMP inhibitor compounds of the present invention may have inhibitory activity (IC ₅₀ MMP-2 and / or MMP-9) in the range of about 0.2 nM to about 20 μM, typically about 1 nM to about 2 μM. The synthesis of MMP inhibitory compounds of the present invention and their biological assays are described in the following examples, which are in no way intended to limit the invention.

Examples and Methods All reagents and solvents are obtained from commercial sources and used without further purification. Proton ( ¹ H) spectra are recorded in deuterated solvents on an NMR spectrometer. Flash chromatography is performed using Merck silica gel, grade 60, 70-230 mesh using an appropriate organic solvent as shown in the specific examples. Thin layer chromatography (TLC) is performed on silica gel plates using UV detection.

  Example 1

工程Ａ
（Ｒ）−２−アミノ−３−（１Ｈ−インドール−３−イル）−プロピオン酸２（０．２３ｇ、１．１２ｍｍｏｌ）（Ａｌｆａ−Ａｅｓａｒ，Ａ−１８４２６）を含むアセトン（３ｍＬ）の懸濁液に、２Ｍ炭酸ナトリウム（１ｍＬ）を添加して室温で３０分間撹拌した。この混合物にブロモスルホニルクロリド１（０．１３ｇ、０．５ｍｍｏｌ）（Ａｌｆａ−Ａｅｓａｒ，Ａ−１４６７７）を０℃で添加し、１５分間撹拌した。反応混合物を室温で１時間さらに撹拌した。水（２０ｍＬ）に注いだ後、溶液をエーテル（×３）で洗浄した。水層を１Ｍ ＨＣｌで酸性化後、酢酸エチル（×３）で抽出した。次いで、合わせた有機抽出物をブラインで洗浄し、乾燥させて（Ｎａ_２ＳＯ_４）、粗（Ｒ）−２−（５−ブロモ−チオフェン−２−スルホニルアミノ）−３−（１Ｈ−インドール−３−イル）−プロピオン酸生成物（３）（０．１６ｇ、７４％）を得た。ＬＣ−ＭＳ（ＥＳ＋）４２９、４３１；（ＥＳ−）４２７、４２９。

Process A
Suspension of acetone (3 mL) containing (R) -2-amino-3- (1H-indol-3-yl) -propionic acid 2 (0.23 g, 1.12 mmol) (Alfa-Aesar, A-18426) To the solution, 2M sodium carbonate (1 mL) was added and stirred at room temperature for 30 minutes. To this mixture was added bromosulfonyl chloride 1 (0.13 g, 0.5 mmol) (Alfa-Aesar, A-14777) at 0 ° C. and stirred for 15 minutes. The reaction mixture was further stirred at room temperature for 1 hour. After pouring into water (20 mL), the solution was washed with ether (x3). The aqueous layer was acidified with 1M HCl and extracted with ethyl acetate (× 3). The combined organic extracts were then washed with brine, dried (Na ₂ SO ₄ ) and crude (R) -2- (5-bromo-thiophen-2-sulfonylamino) -3- (1H-indole- A 3-yl) -propionic acid product (3) (0.16 g, 74%) was obtained. LC-MS (ES +) 429, 431; (ES-) 427, 429.

  A portion of the crude (R) -2- (5-bromo-thiophen-2-sulfonylamino) -3- (1H-indol-3-yl) -propionic acid product (3) was obtained without further purification. Used in the process.

  Example 2

工程Ａ
丸底フラスコ中に粗（Ｒ）−２−（５−ブロモ−チオフェン−２−スルホニルアミノ）−３−（１Ｈ−インドール−３−イル）−プロピオン酸（３）（６０ｍｇ、０．１４ｍｍｏｌ）、ｐ−トリルアセチレン４（４８０ｍｇ、０．４１ｍｍｏｌ）、ＰｄＣｌ_２Ｐ（ＰＰｈ_３）_２（１０ｍｇ、０．０１５ｍｍｏｌ）、ヨウ化銅（Ｉ）（２ｍｇ、０．０１ｍｍｏｌ）、およびトリエチルアミン（０．０２５ｇ、０．２５ｍｍｏｌ）を添加し、次いで、窒素雰囲気下で乾燥ＤＭＦ（２ｍＬ）に溶解した。次いで、反応混合物を、窒素雰囲気下にて５０℃で２時間加熱した。次いで、反応混合物を室温に冷却し、酢酸エチルで希釈し、ＮａＣｌ／ＮａＨＣＯ_３／（ＮＨ_４）_２ＣＯ_３／水（１：１：１：１）から構成される溶液（×３）、水で洗浄し、次いで、硫酸ナトリウム（Ｎａ_２ＳＯ_４）で乾燥させた。粗生成物をＳＡＸカラムを使用して精製して、所望の（Ｒ）−３−（１Ｈ−インドール−３−イル）−２−（５−ｐ−トリルエチニル−チオフェン−２−スルホニルアミノ）−プロピオン酸５（０．０３６ｇ、５５％）を得た。

Process A
Crude (R) -2- (5-bromo-thiophen-2-sulfonylamino) -3- (1H-indol-3-yl) -propionic acid (3) (60 mg, 0.14 mmol) in a round bottom flask, p-Tolylacetylene 4 (480 mg, 0.41 mmol), PdCl ₂ P (PPh ₃ ) ₂ (10 mg, 0.015 mmol), copper (I) iodide ( ₂ mg, 0.01 mmol), and triethylamine (0.025 g, 0.25 mmol) was then added and then dissolved in dry DMF (2 mL) under a nitrogen atmosphere. The reaction mixture was then heated at 50 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, a solution (x3) composed of NaCl / NaHCO ₃ / (NH ₄ ) ₂ CO ₃ / water (1: 1: 1: 1), water And then dried over sodium sulfate (Na ₂ SO ₄ ). The crude product is purified using a SAX column to give the desired (R) -3- (1H-indol-3-yl) -2- (5-p-tolylethynyl-thiophen-2-sulfonylamino)- Propionic acid 5 (0.036 g, 55%) was obtained.

Reaction A of Example 2 was repeated on the same scale as above and then combined with the previous batch. The combined products were then further purified using preparative reverse phase HPLC to give (R) -3- (1H-indol-3-yl) -2- (5-p-tolylethynyl-thiophene-2). -Sulfonylamino) -propionic acid 5 was obtained by HPLC with a purity greater than 95%. LC-MS (ES +) 465; (ES-) 463; ¹ H NMR (300 MHz, DMSO-d6) δ 2.35 (s, 3H), 2.86-2.94 (m, 1H), 3.08-3.16 (m, 1H) 3.96-4.40 (m, 1H), 6.93-7.50 (m, 11H), 8.67 (d, 1H, J = 8.7 Hz), 10.83 (s, 1H).

  Example 3: Synthesis of 4-iodotoluene (D3, 98%) starting material

工程Ａ
Ｇｒｉｅｓｓの古典的方法（Ｐｒａｃｔｉｃａｌ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ，Ｒｉｃｈａｒｄ Ｃｌａｙ ＆ Ｓｏｎｓ，ｐａｇｅ １４４，Ｐｒｅｐａｒａｔｉｏｎ ＃６０，（１９００））に従って、０．２グラム（１．８ｍｍｏｌ）のトルイジン（Ｄ３、９８％）（Ｃ／Ｄ／Ｎ Ｉｓｏｔｏｐｅｓ（Ｑｕｅｂｅｃ，Ｃａｎａｄａ）から購入）（６）を０．４ｍｌのＤ_２ＳＯ_４（Ｃａｍｂｒｉｄｇｅ Ｉｓｏｔｏｐｅ Ｌａｂｏｒａｔｏｒｉｅｓ，Ａｎｄｏｖｅｒ，ＭＡから購入）と合わせ、得られた混合物を、撹拌混合物の温度が０℃に到達するまで冷却し、次いで、１６０ｍｇ（２．３２ｍｍｏｌ）の亜硝酸ナトリウムを、温度が確実に１０℃を超えないように１０分間にわたって３回に分けてゆっくり添加した。亜硝酸ナトリウムの添加後、４８ｍｇ（２．９ｍｍｏｌ）のＫＩを含む１ｍｌのＤ_２Ｏ（Ｃａｍｂｒｉｄｇｅ Ｉｓｏｔｏｐｅ Ｌａｂｏｒａｔｏｒｉｅｓから購入）から構成される溶液を添加し、反応混合物を室温に加温し、１時間撹拌した。次いで、反応混合物をＤ_２Ｏ（１０ｍＬ）で希釈し、エーテル（×２）で抽出した。次いで、エーテル層を１０％Ｎａ_２Ｓ_２Ｏ_３を含むＤ_２Ｏ（×２）で洗浄し、無水硫酸ナトリウムで乾燥させた。次いで、粗生成物（７）を、溶離液としてヘキサンを使用したカラムクロマトグラフィによって精製して、所望の純粋な４−ヨードトルエン（Ｄ３、９８％）生成物（７）（０．１６ｇ、４０％）を得た。¹H NMR(300 MHz,CDCl₃):δ, 6.93(d, 2H,J=7.8 Hz), 7.56(d, 2H, J=7.8 Hz)。

Process A
According to the classical method of Griess (Practical Organic Chemistry, Richard Clay & Sons, page 144, Preparation # 60, (1900)), 0.2 grams (1.8 mmol) of toluidine (D3, 98%) (C / D / N Isotopes (purchased from Quebec, Canada) (6) was combined with 0.4 ml of D ₂ SO ₄ (purchased from Cambridge Isolaboratories, Andover, MA), and the resulting mixture was brought to a temperature of the stirring mixture at 0 ° C. Cooled until reached, then 160 mg (2.32 mmol) of sodium nitrite was added slowly in three portions over 10 minutes to ensure that the temperature did not exceed 10 ° C. After the addition of sodium nitrite, a solution composed of 1 ml D ₂ O (purchased from Cambridge Isotop Laboratories) containing 48 mg (2.9 mmol) KI was added and the reaction mixture was warmed to room temperature and stirred for 1 hour did. The reaction mixture was then diluted with D ₂ O (10 mL) and extracted with ether (× 2). Next, the ether layer was washed with D ₂ O (× 2) containing 10% Na ₂ S ₂ O ₃ and dried over anhydrous sodium sulfate. The crude product (7) was then purified by column chromatography using hexane as the eluent to give the desired pure 4-iodotoluene (D3, 98%) product (7) (0.16 g, 40% ) ¹ H NMR (300 MHz, CDCl ₃ ): δ, 6.93 (d, 2H, J = 7.8 Hz), 7.56 (d, 2H, J = 7.8 Hz).

When D ₂ SO ₄ was replaced with DCl (purchased from Cambridge Isotop Laboratories, Andover, MA), the yield of 7 was only 20%.

  Example 4

工程Ａ
丸底フラスコ中に粗化合物（Ｒ）−２−（５−ブロモ−チオフェン−２−スルホニルアミノ）−３−（１Ｈ−インドール−３−イル）−プロピオン酸生成物（３）（０．２５ｇ、０．５８４ｍｍｏｌ）（実施例１の工程Ａで合成）、市販のエチニルトリメチルシラン（０．１７ｇ、１．７３ｍｍｏｌ）、ＰｄＣｌ_２Ｐ（ＰＰｈ_３）_２（０．０４１ｇ、０．０６１ｍｍｏｌ）、ヨウ化銅（Ｉ）（０．００６ｇ、０．０３１５ｍｍｏｌ）、およびトリエチルアミン（０．１７７ｇ、１．７５ｍｍｏｌ）を添加し、窒素雰囲気下で乾燥ＤＭＦ（３ｍＬ）に溶解し、混合物を５０℃で２時間加熱した。次いで、反応混合物を酢酸エチルで希釈し、ＮａＣｌ／ＮａＨＣＯ_３／（ＮＨ_４）_２ＣＯ_３／水（１：１：１：１）から構成される溶液（×３）、水、ブラインで洗浄し、乾燥させて（Ｎａ_２ＳＯ_４）、所望の粗（Ｒ）−３−（１Ｈ−インドール−３−イル）−２−（５−トリメチルシラニルエチニル−チオフェン−２−スルホニルアミノ）−プロピオン酸８（１８５ｍｇ、７１％）を得た。ＬＣ−ＭＳ（ＥＳ＋）４４７；（ＥＳ−）４４５。

Process A
Crude compound (R) -2- (5-bromo-thiophen-2-sulfonylamino) -3- (1H-indol-3-yl) -propionic acid product (3) (0.25 g, 0.584 mmol) (synthesized in Step A of Example 1), commercially available ethynyltrimethylsilane (0.17 g, 1.73 mmol), PdCl ₂ P (PPh ₃ ) ₂ (0.041 g, 0.061 mmol), iodide Copper (I) (0.006 g, 0.0315 mmol) and triethylamine (0.177 g, 1.75 mmol) are added and dissolved in dry DMF (3 mL) under a nitrogen atmosphere and the mixture is heated at 50 ° C. for 2 hours. did. The reaction mixture is then diluted with ethyl acetate and washed with a solution (x3) consisting of NaCl / NaHCO ₃ / (NH ₄ ) ₂ CO ₃ / water (1: 1: 1: 1), water, brine. , Dried (Na ₂ SO ₄ ), and desired crude (R) -3- (1H-indol-3-yl) -2- (5-trimethylsilanylethynyl-thiophen-2-sulfonylamino) -propionic acid 8 (185 mg, 71%) was obtained. LC-MS (ES +) 447; (ES-) 445.

Process B
Crude (R) -3- (1H-indol-3-yl) -2- (5-trimethylsilanylethynyl-thiophen-2-sulfonylamino) -propionic acid 8 (0.126 g, 0.282 mmol) in dichloromethane / To a solution of the mixture in methanol (1: 1, 10 mL) was added K ₂ CO ₃ (0.047 g, 0.34 mmol) and stirred for 60 minutes. The reaction mixture was then filtered and the residue was washed with a dichloromethane-methanol mixture. The combined filtrate was concentrated under reduced pressure and then purified using a SAX column to give (R) -2- (5-ethynyl-thiophene-2-sulfonylamino) -3- (1H-indole-3- Yl) -propionic acid 9 (52 mg, 49%) was obtained. LC-MS (ES +) 375; (ES-) 373.

Process C
In a round bottom flask, (R) -2- (5-ethynyl-thiophen-2-sulfonylamino) -3- (1H-indol-3-yl) -propionic acid 9 (0.052 g, 0.139 mmol), Iodotoluene- (D3, 98%) 7 (0.061 g, 0.28 mmol) (obtained from commercially available 4-aminotoluene (D3, 98%) by the Sandmeyer reaction outlined in Example 3), PdCl ₂ P [(PPh ₃ )] ₂ (0.01 g, 0.015 mmol), copper (I) iodide (0.002 g, 0.0105 mmol), and triethylamine (0.025 g, 0.247 mmol) were added and dried DMF. (3 mL) was dissolved in a nitrogen atmosphere and the mixture was heated at 50 ° C. for 2 hours. The reaction mixture is cooled, diluted with ethyl acetate and washed with a solution (x3) composed of NaCl / NaHCO ₃ / (NH ₄ ) ₂ CO ₃ / water (1: 1: 1: 1), water, brine And then dried over sodium sulfate (Na ₂ SO ₄ ). The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude 10. This was purified by SAX column chromatography to give purification 10 (0.025 g, 38%). The product was further purified by preparative reverse phase HPLC to yield the desired product 10 (R) -3- (1H-indol-3-yl) -2- [5- (4-trideuteromethyl-phenylethynyl). ) -Thiophen-2-sulfonylamino] -propionic acid- (D3, 98%) was obtained by HPLC with a purity greater than 95%. LC-MS (ES +) 468; (ES-) 466.
¹ H NMR (300 MHz, MeOH-d4) δ 3.17-3.25 (m), 4.32-4.35 (m), 5.60-5.66 (m), 7.05-7.68 (m), 10.4 (br s).

  Example 5

Ｎ−（１−エトキシメトキシメチル−３−ヒドロキシカルバモイル−ブチル）−４−フェノキシ−ベンズアミド（１１）（ＯＮＯ４８１７）を、Ｔｏｃｒｉｓ Ｂｉｏｓｃｉｅｎｃｅｓ（Ｅｌｌｉｓｖｉｌｌｅ，Ｍｉｓｓｏｕｒｉ）から購入することができる。

N- (1-ethoxymethoxymethyl-3-hydroxycarbamoyl-butyl) -4-phenoxy-benzamide (11) (ONO4817) can be purchased from Tocris Biosciences (Ellisville, Missouri).

  Example 6

Ｎ−［４−（３−チイラニルメタンスルホニル−フェノキシ）−フェニル］−メタンスルホンアミド（N-[4-(3-Thiiranylmethanesulfonyl-phenoxy)-phenyl]-methanesulfonamide）（１２）（Ｌｉｐｔｏｎら、ＷＯ２００６／０３６９２８およびＩｋｅｊｉｒｉ，Ｍ．ら、Ｊｏｕｒｎａｌ ｏｆ Ｂｉｏｌｏｇｉｃａｌ Ｃｈｅｍ．，２８０，３３９９２，（２００５））を、ＥＭＤ Ｂｉｏｓｃｉｅｎｃｅｓ，Ｉｎｃ．（Ｇｉｂｂｓｔｏｗｎ，ＮＪ）から購入することができる。

N- [4- (3-Thiranylmethanesulfonyl-phenoxy) -phenyl] -methanesulfonamide (N- [4- (3-Thiiranylmethanesulfonyl-phenoxy) -phenyl] -methanesulfonamide) (12) (Lipton et al., WO2006 / 036928 and Ikejiri, M. et al., Journal of Biological Chem., 280, 33992, (2005)), EMD Biosciences, Inc. (Gibbown, NJ).

  Example 7

２−（３−フェノキシ−ベンゼンスルホニルメチル）−チイラン（１３）（Ｌｉｐｔｏｎら、ＷＯ２００６／０３６９２８およびＫｌｅｉｆｅｌｄ，Ｏ．ら、Ｊｏｕｒｎａｌ ｏｆ Ｂｉｏｌｏｇｉｃａｌ Ｃｈｅｍ．，２７６，１７１２６，（２００１））を、ＥＭＤ Ｂｉｏｓｃｉｅｎｃｅｓ，Ｉｎｃ．（Ｇｉｂｂｓｔｏｗｎ，ＮＪ）またはＢｉｏｍｏｌ（Ｐｙｍｏｕｔｈ Ｍｅｅｔｉｎｇ，ＰＡ）から購入することができる。

2- (3-phenoxy-benzenesulfonylmethyl) -thiirane (13) (Lipton et al., WO 2006/036928 and Kleifeld, O. et al., Journal of Biological Chem., 276, 17126, (2001)) was purchased from EMD Biosciences, Inc. . (Gibbown, NJ) or Biomol (Pymout Meeting, PA).

  Example 8

４−（４’−クロロ−ビフェニル−４−イル）−４−オキソ−２−フェニルスルファニルメチル−酪酸（１４）（タノマスタット）を、Ｔｏｒｏｎｔｏ Ｒｅｓｅａｒｃｈ Ｃｈｅｍｉｃａｌｓ，Ｉｎｃ．（Ｏｎｔａｒｉｏ，Ｃａｎａｄａ）またはＴｅｘａｓ Ｂｉｏｃｈｅｍｉｃａｌｓ，Ｉｎｃ．（Ｃｏｌｌｅｇｅ Ｓｔａｔｉｏｎ，ＴＸ）から購入することができるか、文献に記載の手順（（Ｋｌｕｅｎｄｅｒ Ｈ．ら、ＵＳ ５８８６０２２（１９９９））によって合成することができる。

4- (4′-Chloro-biphenyl-4-yl) -4-oxo-2-phenylsulfanylmethyl-butyric acid (14) (Tanomastert) was purchased from Toronto Research Chemicals, Inc. (Ontario, Canada) or Texas Biochemicals, Inc. Can be purchased from (College Station, TX) or can be synthesized by procedures described in the literature ((Kluender H. et al., US 5886022 (1999)).

  Example 19

２−（４’−ブロモ−ビフェニル−４−スルホニル）−３−メチル−酪酸（１５）［ＰＤ １６６７９３］］を、Ｔｏｃｒｉｓ Ｂｉｏｓｃｉｅｎｃｅｓ（Ｅｌｌｉｓｖｉｌｌｅ，Ｍｉｓｓｏｕｒｉ）から購入することができる。

2- (4′-bromo-biphenyl-4-sulfonyl) -3-methyl-butyric acid (15) [PD 166793]] can be purchased from Tocris Biosciences (Ellisville, Missouri).

  Example 10

２−［２−メルカプト−４−（３，４，４−トリメチル−２，５−ジオキソ−イミダゾリジン−１−イル）−ブチリルアミノ］−４−メチル−ペンタン酸（２，２−ジメチル−１−メチルカルバモイル−プロピル）−アミド（１６）［レビマスタットまたはＢＭＳ−２７５２９９１］（Ｆｒａｎｃｅ，Ｓ．；Ｏｒｇａｎｉｃ Ｌｅｔｔｅｒｓ，２００５（７（１４），３００９，（２００５））を、Ｆｉｎｅｃｈｅｍｉｅ ＆ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ．（Ｃｈｏｎｇｑｕｉｎｇ，Ｃｈｉｎａ）またはＣｈｉｎａ ＣＳＰＣ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｇｒｏｕｐ（Ｓｈｉｊｉａｚｈｕａｎｇ，Ｃｈｉｎａ）から購入することができるか、引用した文献に記載の手順（Ｆｒａｎｃｅ，Ｓ．；Ｏｒｇａｎｉｃ Ｌｅｔｔｅｒｓ，２００５（７（１４），３００９，（２００５））によって合成することができる。

2- [2-Mercapto-4- (3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl) -butyrylamino] -4-methyl-pentanoic acid (2,2-dimethyl-1- Methylcarbamoyl-propyl) -amide (16) [Levimasterat or BMS-2752991] (France, S .; Organic Letters, 2005 (7 (14), 3009, (2005)) was prepared by Finechemie & Pharma Co., Ltd. Chongqing, China) or China CSPC Pharmaceutical Group (Shijiazuhang, China) or procedures described in the cited literature (France, S .; Organic Letters, 2005 (7 14), 3009, can be synthesized by (2005)).

  Example 11

３，１０，１２，１２ａ−テトラヒドロキシ−１，１１−ジオキソ−１，４，４ａ，５，５ａ，６，１１，１２ａ−オクタヒドロ−ナフタセン−２−カルボン酸アミド（１７）（Ｒｕｄｅｋ，Ｍ．ら、Ｊ．Ｃｌｉｎｉｃａｌ Ｏｎｃｏｌｏｇｙ，１９，５８４−５９２（２００１））を、Ｓｉｇｍａ−Ａｌｄｒｉｃｈ（Ｍｉｌｗａｕｋｅｅ，Ｗｉｓｃｏｎｓｉｎ）から入手することができる。

3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a, 5,5a, 6,11,12a-octahydro-naphthacene-2-carboxylic acid amide (17) (Rudek, M .; J. Clinical Oncology, 19,584-592 (2001)) can be obtained from Sigma-Aldrich (Milwaukee, Wisconsin).

  Example 12

４−ジメチル（Ｄ６，９８％）アミノ−３，１０，１２，１２ａ−テトラヒドロキシ−１，１１−ジオキソ−１，４，４ａ，５，５ａ，６，１１，１２ａ−オクタヒドロ−ナフタセン−２−カルボン酸アミド（１８）を、Ｔｏｒｏｎｔｏ Ｒｅｓｅａｒｃｈ Ｃｈｅｍｉｃａｌｓ，Ｉｎｃ．（Ｏｎｔａｒｉｏ，Ｃａｎａｄａ）から入手することができる。

4-Dimethyl (D6, 98%) amino-3, 10, 12, 12a-tetrahydroxy-1,11-dioxo-1,4,4a, 5,5a, 6,11,12a-octahydro-naphthacene-2- Carboxylic acid amide (18) was obtained from Toronto Research Chemicals, Inc. (Ontario, Canada).

  Example 13

４−ジメチルアミノ−３，１０，１２，１２ａ−テトラヒドロキシ−１，１１−ジオキソ−１，４，４ａ，５，５ａ，６，１１，１２ａ−オクタヒドロ−ナフタセン−２−カルボン酸アミド（１９）（Ｓａｎｃｙｃｌｉｎｅ）を、Ｔｏｒｏｎｔｏ Ｒｅｓｅａｒｃｈ Ｃｈｅｍｉｃａｌｓ，Ｉｎｃ．（Ｏｎｔａｒｉｏ，Ｃａｎａｄａ）から入手することができる。

4-Dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a, 5,5a, 6,11,12a-octahydro-naphthacene-2-carboxylic acid amide (19) (Sancycline) from Toronto Research Chemicals, Inc. (Ontario, Canada).

  Example 14

２−［２−（４’−クロロ−ビフェニル−４−イル）−２−オキソ−エチル］−５−（１，３−ジオキソ−１，３−ジヒドロ−イソインドール−２−イル）−ペンタン酸（２０）を、文献に記載の手順（Ｋｌｕｅｎｄｅｒ Ｈ．ら、米国特許第５８８６０２２号（１９９９）；実施例１８９）によって合成することができる。

2- [2- (4′-Chloro-biphenyl-4-yl) -2-oxo-ethyl] -5- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -pentanoic acid (20) can be synthesized by literature procedures (Kluender H. et al., US Pat. No. 5,886,022 (1999); Example 189).

  Example 15

２−｛４’−［（１Ｈ−ベンゾイミダゾール−２−カルボニル）−アミノ］−ビフェニル−４−スルホニルアミノ｝−３−メチル−酪酸（２１）を、文献に記載の手順（Ｌｅｖｉｎ，Ｊ．Ｉ．ら、米国特許第７４２０，００１（Ｂ２）号（２００８））によって合成することができる。

2- {4 ′-[(1H-benzimidazol-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (21) was prepared according to the procedure described in the literature (Levin, J.I. Et al., US Pat. No. 7,420,001 (B2) (2008)).

  Example 16

２−｛４’−［（５−メトキシ−ベンゾフラン−２−カルボニル）−アミノ］−ビフェニル−４−スルホニルアミノ｝−３−メチル−酪酸（２２）を、文献に記載の手順（Ｌｅｖｉｎ，Ｊ．Ｉ．ら、米国特許第７４２０，００１（Ｂ２）号（２００８））によって合成することができる。

2- {4 ′-[(5-methoxy-benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (22) was prepared according to the procedure described in the literature (Levin, J. et al. I. et al., US Patent No. 7420,001 (B2) (2008)).

  Example 17

２−｛４’−［（ベンゾフラン−２−カルボニル）−アミノ］−ビフェニル−４−スルホニルアミノ｝−３−メチル−酪酸（２３）を、文献に記載の手順（Ｌｅｖｉｎ，Ｊ．Ｉ．ら、米国特許第７４２０，００１（Ｂ２）号（２００８））によって合成することができる。

2- {4 ′-[(benzofuran-2-carbonyl) -amino] -biphenyl-4-sulfonylamino} -3-methyl-butyric acid (23) was prepared according to the procedure described in the literature (Levin, J. I. et al., US Pat. No. 7,420,001 (B2) (2008)).

  Example 18

ベンゾフラン−２−カルボン酸４’−（１−カルボキシ−２−メチル−プロピルスルファモイル）−ビフェニル−４−イルエステル（２４）を、文献に記載の手順（Ｌｅｖｉｎ，Ｊ．Ｉ．ら、米国特許第７４２０，００１（Ｂ２）号（２００８））によって合成することができる。

Benzofuran-2-carboxylic acid 4 ′-(1-carboxy-2-methyl-propylsulfamoyl) -biphenyl-4-yl ester (24) was prepared according to the procedure described in the literature (Levin, J. I. et al., USA Patent No. 7420, 001 (B2) (2008)).

  Example 19

４−（４’−ブロモ−ビフェニル−４−スルホニル）−１−メチル−６−オキソ−ピペリジン−３−カルボン酸（２５）を、文献に記載の手順（Ｃｈｕｎｇ，Ｙ．Ｊ．ら、Ｂｕｌｌ．Ｋｏｒｅａｎ Ｃｈｅｍ．Ｓｏｃ．，２９（６），１１０３−１１０４（２００８））によって合成することができる。

4- (4′-Bromo-biphenyl-4-sulfonyl) -1-methyl-6-oxo-piperidine-3-carboxylic acid (25) was prepared according to the procedure described in the literature (Chung, YJ et al., Bull. Korean Chem. Soc., 29 (6), 1103-1104 (2008)).

  Example 20

３−（１Ｈ−インドール−３−イル）−２−［４−（４−メトキシ−フェニルエチニル）−ベンゼンスルホニルアミノ］−プロピオン酸（２６）を、文献に記載の手順（Ｔａｍｕｒａ，Ｙ．ら、Ｊ．Ｍｅｄ．Ｃｈｅｍ．４１，６４０−６４９，（１９９８））によって合成することができる。

3- (1H-Indol-3-yl) -2- [4- (4-methoxy-phenylethynyl) -benzenesulfonylamino] -propionic acid (26) was prepared according to the procedure described in the literature (Tamura, Y. et al., J. Med. Chem. 41, 640-649, (1998)).

  Example 21

３−［２−（４’−シアノ−ビフェニル−４−イル）−ピロール−１−イル］−Ｎ−（２，２−ジメチル−１−メチルカルバモイル−プロピル）−スクシンアミン酸（ｓｕｃｃｉｎａｍｉｃ ａｃｉｄ）（２７）を、文献に記載の手順（Ｗｈｉｔｔａｋｅｒ，Ｍ．ら、Ｃｈｅｍ．Ｒｅｖ．９９，２７３５−２７７６（１９９９）およびその参考文献）によって合成することができる。

3- [2- (4′-Cyano-biphenyl-4-yl) -pyrrol-1-yl] -N- (2,2-dimethyl-1-methylcarbamoyl-propyl) -succinamic acid (27 ) Can be synthesized by procedures described in the literature (Whittaker, M. et al., Chem. Rev. 99, 2735-2776 (1999) and references thereof).

  Example 22

工程Ａ
Ｇｏｌｕｂら（Ｇｏｌｕｂ，Ｌ．Ｍ．ら．，Ｊｏｕｒｎａｌ ｏｆ Ｄｅｎｔａｌ Ｒｅｓｅａｒｃｈ，６６（８），１３１０−１３１４，１９８７）は、テトラサイクリンからのＮ，Ｎ−ジメチルアミン基の化学的除去によって分子から全ての抗菌活性が除去されることを見出した。市販の（Ｓｉｇｍａ−Ａｌｄｒｉｃｈ，Ｍｉｌｗａｕｋｅｅ，ＷＩ）テトラサイクリン（２８）から開始し、次いで、ヨウ化メチルを添加して反応させた場合、ヨウ化トリアルキル中間体（２９）が形成される。

Process A
Golub et al. (Golub, LM, et al., Journal of Dental Research, 66 (8), 1310-1314, 1987) describes all antibacterial activity from the molecule by chemical removal of the N, N-dimethylamine group from tetracycline. It was found that the activity was removed. When starting with commercially available (Sigma-Aldrich, Milwaukee, WI) tetracycline (28) and then reacted with addition of methyl iodide, a trialkyl iodide intermediate (29) is formed.

Process B
Intermediate 29 can then be treated with zinc and acetic acid in water to give chemically modified tetracycline (CMT) -1 (30).

  Example 23

工程Ａ
Ｇｒｅｅｎ ａｎｄ Ｂｏｏｔｈの方法（Ｇｒｅｅｎ，Ａ．；Ｂｏｏｔｈ，Ｊ．Ｈ．；Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ，８２（１５），３９５０−３９５３，１９６０）に従う場合、デジメチルテトラサイクリンアナログＣＭＴ−１（３０）を、水中の亜鉛および水酸化アンモニウムで１２α−ヒドロキシル部分を還元的脱離に供して化学修飾されたテトラサイクリン（ＣＭＴ）−７（３１）を得ることができる。

Process A
When following the method of Green and Booth (Green, A .; Booth, JH; Journal of the American Chemical Society, 82 (15), 3950-3953, 1960), the dedimethyltetracycline analog CMT-1 (30) is used. The 12α-hydroxyl moiety can be subjected to reductive elimination with zinc and ammonium hydroxide in water to give chemically modified tetracycline (CMT) -7 (31).

  Example 24

工程Ａ
トリアルキルアンモニウム基の除去に加えて、Ｇｏｌｕｂらの方法（Ｇｏｌｕｂ，Ｌ．Ｍ．ら．，Ｊｏｕｒｎａｌ ｏｆ Ｄｅｎｔａｌ Ｒｅｓｅａｒｃｈ，６６（８），１３１０−１３１４，１９８７）を使用して、位置選択的様式でテトラサイクリン分子の「Ａ」環のＣ_４位に重水素を組み込むこともできる。ヨウ化トリアルキル中間体（２９）を、Ｄ_２Ｏ中の亜鉛および重水素化酢酸で処理してデジメチルアミン，重水素化テトラサイクリンアナログ３２を得ることができる。

Process A
In addition to removal of the trialkylammonium group, in a regioselective manner using the method of Golub et al. (Golub, LM et al., Journal of Dental Research, 66 (8), 1310-1314, 1987). it is also possible to incorporate the deuterium in the C ₄ position of the "a" ring of the tetracycline molecule. The trialkyl iodide intermediate (29) can be treated with zinc and deuterated acetic acid in D ₂ O to give dedimethylamine, deuterated tetracycline analog 32.

Process B
According to the method of Green and Booth (Green, A .; Booth, J. H .; Journal of the American Chemical Society, 82 (15), 3950-3951, 1960) except that deuterated solvents can be used. In some cases, the dedimethyltetracycline analog 32 can be subjected to reductive elimination of the 12α-hydroxyl moiety with zinc and deuterated ammonium hydroxide in D ₂ O to yield deuterated CMT (33).

  Example 25

工程Ａ
Ｓａｊｉｋｉらの研究（Ｓａｊｉｋｉ，Ｈ．ら、Ｓｙｎｔｈｅｔｉｃ Ｌｅｔｔｅｒｓ，Ｎｏ．９，１３８５−１３８８，２００５）を使用する場合、ＣＭＴ（３３）を水素および重水の存在下で炭素上パラジウムで処理してＣＭＴ−７−ｄ１３を得ることができる。次いで、これをＨ_２Ｏで処理してアミドおよびヒドロキシル（ｈｙｒｏｘｙｌ）水素に戻して所望のＣＭＴ−７−ｄ７（３５）を得ることができる。

Process A
When using the work of Sajiki et al. (Sajiki, H. et al., Synthetic Letters, No. 9, 1385-1388, 2005), CMT (33) was treated with palladium on carbon in the presence of hydrogen and heavy water to produce CMT- 7-d13 can be obtained. This can then be treated with H ₂ O to convert it back to amide and hydroxyl hydrogen to give the desired CMT-7-d7 (35).

  Example 26

工程Ａ
Ｙｏｓｈｉｄａら（Ｙｏｓｈｉｄａ，Ｔ．ら、Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ，１０１（８），２０２７−２０３８，１９７９）の方法に従う場合、ＣＭＴ−ｄ８（３２）を重水中パラジウムトリス−トリエチルホスフィンで処理して重水素化ＣＭＴ（３６）を得ることができる。

Process A
When following the method of Yoshida et al. (Yoshida, T. et al., Journal of the American Chemical Society, 101 (8), 2027-2038, 1979), CMT-d8 (32) was treated with palladium tris-triethylphosphine in deuterated water. Deuterated CMT (36) can be obtained.

Process B
CMT (36) can be treated with palladium on carbon in the presence of hydrogen and heavy water to give CMT-4-d13. This can then be treated with H ₂ O and converted back to amide and hydroxyl hydrogen to give the desired CMT-4-d6 (37).

  Example 27

工程Ａ
Ｙｏｓｈｉｄａらの方法（Ｙｏｓｈｉｄａ，Ｔ．ら、Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ，１０１（８），２０２７−２０３８，１９７９）に従う場合、テトラサイクリン（２８）を水素および重水の存在下で炭素上パラジウムで処理し、加熱して、重水素化テトラサイクリン（Ｔｅｔｒａｃｙｌｃｉｎｅ）−ｄ１２を得ることができる。次いで、テトラサイクリン（Ｔｅｔｒａｃｙｌｃｉｎｅ）−ｄ１２をＨ_２Ｏで処理して容易に交換可能なアミドおよびヒドロキシル（ｈｙｒｏｘｙｌ）水素に戻して所望のテトラサイクリン（Ｔｅｔｒａｃｙｌｃｉｎｅ）−ｄ５（３８）を得ることができる。

Process A
When following the method of Yoshida et al. (Yoshida, T. et al., Journal of the American Chemical Society, 101 (8), 2027-2038, 1979), tetracycline (28) is treated with palladium on carbon in the presence of hydrogen and heavy water. And heated to give deuterated tetracycline-d12. Tetracycline-d12 can then be treated with H ₂ O to return it to an easily exchangeable amide and hydroxyl hydrogen to give the desired tetracycline-d5 (38).

  Example 28

工程Ａ
Ｙｏｓｈｉｄａらの方法（Ｙｏｓｈｉｄａ，Ｔ．ら、Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ，１０１（８），２０２７−２０３８，１９７９）に従う場合、化合物（１７）を水素および重水の存在下で炭素上パラジウムで処理し、加熱して重水素化テトラサイクリン−ｄ１２を得ることができる。次いで、テトラサイクリン−ｄ１２をＨ_２Ｏで処理して容易に交換可能なアミドおよびヒドロキシル（ｈｙｒｏｘｙｌ）水素に戻して所望のテトラサイクリン（Ｔｅｔｒａｃｙｌｃｉｎｅ）−ｄ６（３９）を得ることができる。

Process A
When following the method of Yoshida et al. (Yoshida, T. et al., Journal of the American Chemical Society, 101 (8), 2027-2038, 1979), compound (17) is treated with palladium on carbon in the presence of hydrogen and heavy water. To obtain deuterated tetracycline-d12. Tetracycline-d12 can then be treated with H ₂ O to return it to an easily exchangeable amide and hydroxyl hydrogen to give the desired tetracycline-d6 (39).

  Example 29

Ｎ−ヒドロキシ−４−（［４−［４−クロロフェノキシ］ベンゼンスルホニル］メチル）−２，３，５，６−テトラヒドロピラン４−カルボキサミド（４０）（ＲＯ１１３−０８３０またはＣＴＳ−１０２７とも同定されている）を、標準的な文献に記載の手順によって合成することができる（Ｆｉｓｈｅｒ，Ｌａｗｒｅｎｃｅ Ｅ．；Ｄｖｏｒａｋ，Ｃｈａｒｌｅｓ；Ｇｒｅｅｎ，Ｋｅｅｎａ；Ｊａｎｉｓｓｅ，Ｓａｍａｎｔｈａ；Ｐｒｉｎｃｅ，Ａｎｔｈｏｎｙ；Ｓａｒｍａ，Ｋｅｓｈａｂ；ＭｃＧｒａｎｅ，Ｐａｕｌ；Ｍｏｏｒｅ，Ｄａｖｉｄ；Ｃａｍｐｂｅｌｌ，Ｊｅｆｆｒｅｙ；Ｂａｐｔｉｓｔａ，Ｊａｎｅｌ；Ｂｒｏｋａ，Ｃｈｒｉｓ；Ｈｅｎｄｒｉｃｋｓ，Ｔｈａｎ；Ｗａｌｋｅｒ，Ｋｅｉｔｈ；Ｙｅｅ，Ｃａｌｖｉｎ Ｆｒｏｍ Ｂｅｎｃｈ ｔｏ Ｐｉｌｏｔ Ｐｌａｎｔ．ＡＣＳ Ｓｙｍｐｏｓｉｕｍ Ｓｅｒｉｅｓ，Ｖｏｌ．８１７，Ｃｈａｐｔｅｒ ６，（Ａｐｒｉｌ １９，２００２），ｐａｇｅｓ ８９−１００およびその参考文献）。

N-hydroxy-4-([4- [4-chlorophenoxy] benzenesulfonyl] methyl) -2,3,5,6-tetrahydropyran 4-carboxamide (40) (also identified as RO113-0830 or CTS-1027 Can be synthesized by procedures described in standard literature (Fisher, Lawrence E .; Dvorak, Charles; Green, Keena; Janisse, Samantha; Prince, Anthony; Salma, Keshab; McGlane, Paul; Moor; Campbell, Jeffrey; Baptista, Janel; Broka, Chris; Hendricks, Than; Walker, Keith; Yee, Calvin Fro Bench to Pilot Plant.ACS Symposium Series, Vol.817, Chapter 6, (April 19,2002), pages 89-100 and references therein).

Example 105
In-vitro assay to determine microsomal stability of selected compounds in human and mouse microsomes Human and mouse microsomal stability was determined by the method of Houston (Hoston, JB; Biochem. Pharmacol. 47, (1994). ), 1469) for selected compounds. Compounds at 1 μM concentration and individual human and mouse microsomes (0.3 mg / mL, BD bioscience) were used in the in-vitro assay. In order to ensure an adequate energy supply for the microsomal degradation of the compound, an energy regeneration system composed of 100 mM potassium phosphate, 2 mM NADPH, 3 mM MgCl ₂ (pH = 7.4), and microsomal protein is used for each sample. And the resulting suspension is incubated in a rotary shaker at 37 ° C. for 60 minutes in duplicate. In order to detect NADPH-free degradation, controls for each test drug excluding NADPH are performed in duplicate. At T = 0 and T = 60 minutes, aliquots are removed from each experimental and control reaction and consisted of an equal volume of ice-cold stop solution (consisting of 0.3% acetic acid in acetonitrile containing haloperidol and diclofenac (as internal standard)). Mix with. The reaction stop is then incubated at −20 ° C. for at least 10 minutes, and then an additional volume of water is added. The sample is then centrifuged to remove the precipitated protein and the supernatant is then analyzed by LC-MS / MS to determine the residual rate of the compound. The LC-MS / MS system used was an Agilent 6410 mass spectrometer (all controlled by MassHunter software (Agilent)) or an Agilent 1100 HPLC and CTC PAL cooled autosampler connected to an Agilent 1200 HPLC and CTC PAL cooled autosampler. ABI 2000 mass spectrometer (all controlled by Analyst software (ABI)). After separation on a C18 reverse phase HPLC column (Agilent, Waters or equivalent) using an acetonitrile-water gradient system, the peaks were analyzed by mass spectrometry (MS) using ESI ionization in MRM mode.

  Tables 1 and 2 below show the microsomal stability of selected compounds in both human and mouse microsomes.

神経因性疼痛阻害の測定−（ＳＮＬ）−マウス動物モデル：
動物モデルの背景および説明
本発明のＭＭＰインヒビターの神経因性疼痛阻害効果を測定するために、脊髄神経結紮（ＳＮＬ）マウスモデルを、選択した化合物について使用した。Ｂｅｎｎｅｔらの研究（Ｂｅｎｎｅｔ，Ｇ．Ｊ．ら、Ｐａｉｎ，３３，（１９８８），８７−１０７）から開始し、ＫｉｍおよびＣｈｕｎｇ（Ｋｉｍ，Ｓ．Ｈ．；Ｃｈｕｎｇ，Ｊ．Ｍ．Ｐａｉｎ，５０，（１９９２），３５５−３６３）によって最適化されたこのモデルは、マウスにおいて最初に固定し、拡大下で横突起の１／３を除去し、同定し、次いで、切開して隣接するＬ４脊髄神経からＬ５脊髄神経を遊離させた。次いで、Ｌ５脊髄神経を、６．０絹糸縫合を使用して強く結紮する。神経損傷は痛覚過敏を誘導し、この痛覚過敏自体が機械的な熱刺激および／または冷却刺激に対する応答の増強を示す。この場合、機械的痛覚過敏を、種々の厚さおよび曲げ力のフィラメントをマウスの足底面に個別に印加するフォンフライ（ｖｏｎ Ｆｒｅｙ）モノフィラメントによって試験する。神経手術後に足を引っ込めるのに必要な力の閾値が劇的に減少する。強力な疼痛インヒビターは、この影響を逆転させてげっ歯類の足を引っ込めさせるために必要な力をより大きくする。

Measurement of neuropathic pain inhibition-(SNL)-Mouse animal model:
Animal Model Background and Description To determine the neuropathic pain inhibitory effects of the MMP inhibitors of the present invention, a spinal nerve ligation (SNL) mouse model was used for selected compounds. Beginning with the work of Bennet et al. (Bennet, GJ et al., Pain, 33, (1988), 87-107), Kim and Chung (Kim, SH; Chung, JM Pain, 50, (1992), 355-363), this model was first fixed in mice, 1/3 of the transverse process was removed and identified under magnification, then incised and adjacent L4 spinal nerves From which the L5 spinal nerve was released. The L5 spinal nerve is then strongly ligated using 6.0 silk suture. Nerve damage induces hyperalgesia, which itself shows an enhanced response to mechanical thermal and / or cooling stimuli. In this case, mechanical hyperalgesia is tested by von Frey monofilaments in which filaments of various thicknesses and bending forces are individually applied to the sole of the mouse. The threshold force required to retract the foot after neurosurgery is dramatically reduced. Powerful pain inhibitors increase the force required to reverse this effect and retract the rodent foot.

  Example 110: (SNL) —Intrathecal (it) administration of an MMP inhibitor in a pain mouse model.

  After baseline (day -2) paw threshold measurements before surgery, male FVB mice were subjected to SNL injury (day -1). The day after SNL surgery (Day 0), these animals were tested for post-operative baseline threshold measurements for mechanical allodynia, and these animals were then placed in one of three treatment groups. Assigned randomly (see Table 3). Over a series of studies, the paw withdrawal threshold of these animals was measured in response to mechanical stimulation using the von Frey monofilament test.

  To circumvent the systemic effects of MMP inhibitors, the MMP inhibitors of the present invention were delivered into the cerebrospinal fluid (CSF) space around the lumbosacral spinal cord by intrathecal (it) administration (DRG, spinal cord, And to target MMPs in spinal cord CSF). Intrathecal MMP inhibitor administration could then target not only spinal cells but also DRG cells. Each intrathecal (it) injection was performed according to the technique of Hylden and Wilcox (Hylden JL, Wilcox GL. Eur. J Pharmacol., 67, (1980), 313-6). 5.2 mg of each MMP inhibitor is first dissolved in 140 microliters of DMSO and then placed in 1260 microliters of 0.5% hydroxypropylcellulose (HPC) aqueous solution containing 10% DMSO-0.5% containing the compound A fine particle suspension composed of hydroxypropylcellulose was prepared. Ten microliters of the mixture was injected into male FVB mice (22-25 grams each, Jackson Laboratories, body weight 22-25 grams) by lumbar puncture of 10 μl volume / mouse using a 30 gauge needle of a Hamilton microinjector inserted between lumbar spines 5 and 6. , Obtained from Bar Harbor, Me). Briefly, a needle was inserted into the tissue on the right side of the L5 or L6 spinous process while holding each animal's waistband firmly with one hand. The needle was advanced and slid into the groove between the spinous and transverse processes and slowly advanced into the intervertebral space at an angle of about 10 °. A tail flick was noted as the needle was inserted into the spinal column (approximately 0.5 cm) and then the solution was injected. Table 3 summarizes the various treatment groups and dosing frequencies.

接触性異痛症試験。機械的異痛症を、目盛り付きフォンフライフィラメント（セムズ−ワインスタインモノフィラメント；Ｓｔｏｅｌｔｉｎｇ，Ｗｏｏｄ Ｄａｌｅ，ＩＬ，Ｕ．Ｓ．Ａ．）を使用して測定した。各動物の損傷した左足の足底面を、Ｃｈａｐｌａｎら（Ｊｏｕｒｎａｌ ｏｆ Ｎｅｕｒｏｓｃｉｅｎｃｅ Ｍｅｔｈｏｄｓ，５３，（１９９４），５５−６３）に記載のように試験した。５０％足引き閾値応答を、Ｄｉｘｏｎの「上げ下げ法」（Ａｎｎｕａｌ Ｒｅｖｉｅｗ Ｐｈａｒｍａｃｏｌｏｇｙ Ｔｏｘｉｃｏｌｏｇｙ，２０，（１９８０），４４１−４６２）に従って刺激強度を連続的に増減させることによって決定した。マウスについて、ほぼ等しく対数的に増加する曲げ力を有する８本のフォンフライフィラメントを使用した（フォンフライ番号：１．６５、２．３６、２．４４、２．８３、３．２２、３．６１、３．８４、４．０８、および４．１７；それぞれ０．００５、０．０２、０．０３、０．０７、０．１７、０．４１、０．６９、１．２０、および１．４８ｇの力に等しい）。

Contact allodynia test. Mechanical allodynia was measured using calibrated von Frey filaments (Sems-Weinstein monofilament; Steeling, Wood Dale, IL, USA). The plantar surface of each animal's damaged left foot was examined as described in Chaplan et al. (Journal of Neuroscience Methods, 53, (1994), 55-63). The 50% drag threshold response was determined by continuously increasing or decreasing the stimulus intensity according to Dixon's “Raising and Lowering Method” (Annual Review Pharmacology Toxicology, 20, (1980), 441-462). For mice, 8 von Frey filaments with approximately equal logarithmically increasing bending forces were used (von Frey number: 1.65, 2.36, 2.44, 2.83, 3.22, 3.2. 61, 3.84, 4.08, and 4.17; 0.005, 0.02, 0.03, 0.07, 0.17, 0.41, 0.69, 1.20, and 1 respectively. .Equal to .48 g force).

  Prior to the test, each animal was housed in a clear plastic chamber with a wire mesh bottom and acclimated for 15 minutes. The test was started by applying perpendicular to the plantar surface of the hind paw affected at 0.07 g (handle display 2.83), and each filament was applied with sufficient pressure to obtain a bending effect. A heavier filament was used when no foot lift / retraction was observed after 6 seconds. Weaker filaments were used, with a pull showing a positive response. After the first positive response (ie, a pull), the test was continued for 4 additional measurements and used to calculate the response threshold. Four consecutive positive responses were scored at 0.001 g and five consecutive negative responses (ie no tow) were scored at 1.5 g.

Analysis of contact allodynia test. The 50% drag threshold is the formula:
10 (Xf + κδ) / 10,000
Where Xf is the last used von Frey filament (logarithmic unit), κ is the value analyzing the response pattern (taken from the table published by Chaplan et al., 1994), and δ is the mean between stimuli (PWT; Luo and Calcutt, J. Pharmacology Experimental Therapeutics, 303 (3), (2002), 1199-1205; Chaplan et al, Journal of Neuroce 53 (1994), 55-63).

Bias control. To prevent bias in study results, technical staff assessed animal behavioral responses while unaware of each animal's treatment history.
The results of the behavioral test shown in Table 4 clearly show an almost complete reversal of allodynia by Compound No. 10 compared to vehicle and Compound No. 5.

実施例１１１：（ＳＮＬ）−疼痛マウスモデルにおけるＭＭＰインヒビターの腹腔内（ｉ．ｐ．）投与
本発明のＭＭＰ化合物を脊髄領域の外側に投与した場合の本発明のＭＭＰ化合物の生物学的利用能をさらに確認するために、ＳＮＬ−マウスモデルに、化合物番号５および１０の腹腔内投与を繰り返した。投与様式、マウス／群の数、ならびに投与した化合物の注射数および注射あたりの量を除いて、残りの研究（手術ならびに接触性異痛症の試験および分析に関して）を実験１１０と同一の様式で行った。３．２ｍｇの各ＭＭＰインヒビター番号５および１０を、３２０マイクロリットルのＤＭＳＯに溶解した。次いで、この溶液に、３２マイクロリットルのＴｗｅｅｎ ８０、その後に２８５０マイクロリットルのリン酸緩衝化食塩水（ＰＢＳ）を添加した。これは、最終濃度１０％のＤＭＳＯ、１％のＴｗｅｅｎ、および１ｍｇ／ｍｌの化合物を与えた。次いで、ほぼ３．３ｍｇ／Ｋｇの用量を与えるためにマウス１日あたり０．１ｍｌのこの溶液を注射した（連続して５日間）。処置群を表５に概説する。行動試験の結果を、表６に認めることができる。化合物番号１０が５日目までに機械的異痛症（ａｌｏｄｙｎｉａ）の完全な逆転を示すことが明らかである。最後の注射（４日目）から４８時間後（６日目）でさえも化合物番号１０によって比較的長期の効果が発揮されることを示すことが興味深い。

Example 111: (SNL)-Intraperitoneal (ip) Administration of MMP Inhibitors in a Pain Mouse Model Bioavailability of MMP Compounds of the Invention When MMP Compounds of the Invention are Administered Outside the Spinal Cord Area In order to further confirm this, intraperitoneal administration of compound numbers 5 and 10 was repeated in the SNL-mouse model. Except for the mode of administration, the number of mice / group, and the number of injected compounds and the amount per injection, the rest of the study (with regard to surgery and contact allodynia testing and analysis) was done in the same manner as in Experiment 110. went. 3.2 mg of each MMP inhibitor number 5 and 10 was dissolved in 320 microliters DMSO. To this solution was then added 32 microliters of Tween 80 followed by 2850 microliters of phosphate buffered saline (PBS). This gave a final concentration of 10% DMSO, 1% Tween, and 1 mg / ml compound. The mice were then injected with 0.1 ml of this solution per day to give a dose of approximately 3.3 mg / Kg (5 consecutive days). Treatment groups are outlined in Table 5. The results of the behavioral test can be seen in Table 6. It is clear that Compound No. 10 shows a complete reversal of mechanical allodynia by day 5. It is interesting to show that compound no. 10 exerts a relatively long-term effect even 48 hours (day 6) after the last injection (day 4).

実施例１２０
炎症性疼痛阻害の測定−ラットにおけるカラギーナン（ｃａｒｒａｇｅｅｎａ）（ＣＡＲＲ）誘発炎症。

Example 120
Measurement of Inflammatory Pain Inhibition-Carrageena (CARR) induced inflammation in rats.

  When measuring the inflammatory pain inhibitory effect of the MMP inhibitor of the present invention, LaBuda, C. et al. J. et al. , And Fuchs, P.M. N. A carrageenan model for measuring neuropathic pain can be used as shown in Neuroscience Letters, 304, (2001), 137-140.

  Acute model: Subcutaneous injection into the hind paw of rats: Acute inflammatory condition is obtained by subcutaneous injection of 3% λ carrageenan (0.12 ml) into the plantar surface of one hind paw under light isoflurane anesthesia. There is usually an additional control group that receives the same volume of saline. The animals are then administered an MMP inhibitor of the invention three and a half hours after CARR injection. Pain behavior can then be quantified with the paw animal model using the same procedure outlined in experiments 110 and 111.

  Chronic model: intra-articular injection. Longer lasting inflammatory conditions are obtained by intra-articular injection of CARR (0.1 ml, 3%) into the tibial joint under isoflurane anesthesia. This route of administration induces an inflammatory condition that can persist up to 7 days after injection, establishing an inflammatory pain model for arthritis. Pain behavior can then be quantified using the same procedure outlined in experiments 110 and 111.

Example 125
Mouse study of morphine tolerance and naloxone-induced morphine withdrawal.

  Matrix metalloproteinase (MMP) or intraperitoneal (ip) administration of a matrix metalloproteinase (MMP) inhibitor in a mouse model of morphine analgesia, tolerance, and withdrawal The impact can be measured. Its purpose is to measure the effects of MMP inhibitors on withdrawal behavior in 1) reducing morphine tolerance in mice and 2) naloxone-induced morphine withdrawal in mice. An animal model developed in the 1960s and improved in the early 1970s uses the opioid antagonist naloxone to rapidly block μ-opioid receptors and “trigger” withdrawal behavior in rodents ( Zachariou, V. et al .; Essential role for RGS9 in opiate action, PNAS, 100 (23), p 13656-13661, (2003)). Based on the work of Song et al. (The Journal of Neuroscience, 30 (22), (2010), 7613-7623), male and female adult CD-1 mice (Charles River Laboratories) and wild type (WT) FVB mice ( The Jackson Laboratory (8-24 weeks old with a body weight of 24-28 g) was used. Song et al. Used a hot plate apparatus for pain threshold and morphine analgesia / tolerance testing. A cut-off time of 30 seconds was set to avoid tissue damage. Adult Kunming (KM) mice were also used as further confirmation of the behavioral effects of administration of matrix metalloproteinase-2 inhibitor and matrix metalloproteinase-9 inhibitor on other mouse strains.

  Drug administration and morphine withdrawal studies: Matrix metalloproteinase (MMP) inhibitors were dissolved in phosphate buffered saline (PBS) and dimethyl sulfoxide (DMSO) and diluted with PBS (final DMSO for intrathecal administration) The concentration was 10%). Optimally, the MMP inhibitor was first dissolved in DMSO and then diluted with PBS and 1% tween to a final concentration in PBS buffer of 10% DMSO, 1% Tween. Administration of MMP inhibitor (5-10 μg) and vehicle controls, PBS and DMSO, L4-5 and L5-6 for multiple injections using a stainless steel needle (30 gauge) attached to a 25 μl Hamilton syringe Were performed by lumbar puncture in the intervertebral space by injecting intrathecally (IT) (10 μl each) under short-term inhalation of anesthesia for about 5 minutes after each morphine injection. Zachariou et al. (Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, Neve RL, Sim-Selly LJ, Selly V, George SJ, Nest S, Proc. (1003), p. 13656-13661) and the study of Liu et al. (Liu WT, Li HC, Song XS, Huang ZJ, Song XJ, FASEB J 23, (2009), p. 90-98). Escalating doses of morphine (20, 40, 60, 80, 100, and 100 mg / kg) every 8 hours for 2.5 days. p. (See Table 7 for study protocol). Two hours after the last morphine injection, naloxone (1 mg / kg) was given s. c. Administered. The withdrawal behavior was then monitored for 30 minutes 1 hour after naloxone injection. Naloxone is a mu-opioid receptor competitive antagonist that can be used to antagonize the effects of morphine and initiate morphine withdrawal in mice.

モルヒネ離脱に及ぼすＭＭＰインヒビターの影響。髄腔内ＭＭＰインヒビター投与後のモルヒネ離脱様行動的徴候を試験するために、離脱症状をナロキソン投与の１〜２時間後に３０分間モニタリングした。各離脱徴候の測定に加えて、総合アヘン剤離脱スコアを、Ｓｏｎｇら（Ｔｈｅ Ｊｏｕｒｎａｌ ｏｆ Ｎｅｕｒｏｓｃｉｅｎｃｅ，３０（２２），（２０１０），７６１３−７６２３）およびその他（Ｚａｃｈａｒｉｏｕら、２００３；Ｌｉｕら、２００９ａ）の研究から得た計算式（（後方歩行数×０．１）＋（下痢×２）＋（ジャンプ数×０．１）＋（足の震え×０．１）＋下垂＋震え＋（体重減少％×５）＋身震い（wet-dog shake）の数）を使用して計算した。結果は、化合物１０がコントロールおよびビヒクルと比較して全モルヒネ離脱行動を軽減することができることを示した（図１のＡ〜Ｊを参照のこと）。

Effect of MMP inhibitor on morphine withdrawal. To test for morphine withdrawal-like behavioral signs following intrathecal MMP inhibitor administration, withdrawal symptoms were monitored for 30 minutes 1-2 hours after naloxone administration. In addition to measuring each withdrawal sign, the total opiate withdrawal score was determined by Song et al. (The Journal of Neuroscience, 30 (22), (2010), 7613-7623) and others (Zachariou et al., 2003; Liu et al., 2009a). Formula obtained from the study of (number of backward walking × 0.1) + (diarrhea × 2) + (number of jumps × 0.1) + (foot tremor × 0.1) + drooping + tremor + (weight loss % X 5) + number of wet-dog shakes). The results showed that compound 10 can reduce total morphine withdrawal behavior compared to control and vehicle (see AJ in FIG. 1).

Gelatin zymography for measurement of any MMP-2 and / or MMP-9 rebound effect MMP-2 and MMP in mouse spinal cord (including segments L1-L6) before, during and after administration of Compound 10 To determine the level of -9, gelatin zymography was performed according to the method of Song et al. (The Journal of Neuroscience, 30 (22), (2010), 7613-7623). The purpose of this study was to investigate whether there is any MMP-2 and / or MMP-9 rebound effect due to withdrawal of Compound 10 in a naloxone-induced withdrawal animal model. There were three groups in the study involving 6 mice for each group (naive, control, and compound 10 groups). Results showed that MMP-2 and MMP-9 levels remained the same 0.5 hours and 2 hours after naloxone-induced withdrawal and withdrawal of Compound 10 administration or control (compound 10 administered but not undergoing withdrawal) It was slightly lower than the group of mice. There was no evidence of a rebound effect of MMP-2 and / or MMP-9 due to compound 10 interruption.

  Effect of MMP inhibitors on reducing morphine pain blockade. To test the effects of MMP inhibitors on pain threshold and the initial response of analgesics to morphine, mice can be placed on a hot plate apparatus at 55 ° C. and the latency to lick the paw can be measured. Data can be calculated as a percentage of maximum possible effect (MPE%). This MPE% is calculated by the Song et al. Formula (The Journal of Neuroscience, 30 (22), (2010), 7613-7623) (the following formula: 100 × [(drug response time−basic response time) / (30 seconds− Basic response time)] = MPE%). Morphine (10 mg / kg, sc), MMP inhibitor (5-10 μg, it), and control vehicles PBS and DMSO (1%, it) were given 30 minutes before the test. Can be administered. The protocol is identical to the protocol described by the group of Song et al., Zachariou et al., And Liu et al. In order to assess physical resistance to morphine, each mouse was placed on a hot plate apparatus at 55 ° C. and the latency until licking the paw after subcutaneous injection of morphine was measured. For acute tolerance testing, the latency to licking the paw was 0.5, 1, 1.5, 10 mg / kg single dose morphine dose administered 24 hours after 100 mg / kg morphine treatment. And can be measured after 2 hours. Chronic tolerance can be tested after repeated treatment of morphine 10 mg / kg daily for 7 days and the analgesic effect can be measured 30 minutes after each injection.

Example 126
Self-administered rodent model for addiction: A study of recurrence initiated by cues: MMP-2 for recurrence initiated by cues associated with self-administration of addictive substances (such as opioids, amphetamines, alcohol, nicotine, or cocaine) And evaluation of MMP-9 inhibitors. This animal model is based on addictiveness in ascetic rats who have previously had a history of self-administration of addictive drugs, exposure to cues previously associated with addictive drugs (such as opioids, amphetamines, alcohol, nicotine, or cocaine). Based on the idea that drug-seeking behavior can be recurred (Shelton, KL; Beardsley, PM; ), 434-440, (2008)). This effect is thought to be similar to clinical cases where re-exposure to the environment and drug tools induces recurrence to substance addiction. Chemicals that undermine the effectiveness of revitalizing the search for addictive substances by this method are considered promising as potential drugs to prevent recurrence of substance abusers. Twelve male rats (Long-Evans) can be used to evaluate each dose of MMP-2 inhibitor and / or MMP-9 inhibitor or vehicle that can be administered orally. After habituation to the incubator, an indwelling venous catheter can be implanted in the right external jugular vein. The rats were then allowed to recover from surgery at least 5 days before the start of self-administration training. A self-administration training session with 0.1 mg / kg / infusion addictive substance is available for 2 hours a day. At the beginning of the addictive drug self-administration session, the lever is extended and house light is irradiated. During training, each of the right lever presses infuses addictive drugs for 6 seconds, followed by a 14 second timeout period. At the start of injection, the house light is turned off, the Sonalert sounds, and the cue light above each lever shines at a frequency of 3 Hz. Sonalert and cuelite remain activated during the 6 second infusion. The houselight can be re-irradiated 20 seconds after the start of the infusion and the opportunity to self-administer addictive drugs is regained (ie, each addictive drug infusion can be started for 20 seconds, during which the lever Can be recorded, but planned results are not obtained and no further injections can be made). Twelve rats can be used to evaluate each oral dose of MMP-2 inhibitor and / or MMP-9 inhibitor or vehicle.

  Other rodent models involved in addictive substance self-administration: Each rat is trained to depress two levers equally in the operant chamber. After training, one lever can be randomly assigned as the active lever, and the other lever can be inactive. Self-administration studies of addictive substances (such as nicotine or methamphetamine) can be initiated about 7 days after implantation of the jugular vein catheter. For the study of the enhancement effect of nicotine, animals are s. c. It can react to unconditional non-drug-enhancing factors (eg, light or sound) in the presence or absence of nicotine delivered via injection. Other behavioral paradigms may include a co-selection procedure that allows animals to acquire nicotine (ie, cocaine, methylamphetamine, opioids, etc.) and non-drug-enhancing factors in the same session (Palmatier, MI, F., et al. F.Evans-Martin, et al. (2006). "Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine or some other addictive substance using a rat self-administration paradigm with concurrently available drug and environmental reincers. "Psychopharmacology (Berr) 184 (3-4): 391-400.). Conditioned place preference is used to compliment self-administration studies, and the desire for contextual stimuli associated with addictive substances (ie, nicotine, amphetamine, cocaine, or opioids) is an MMP-2 inhibitor and / or MMP- It can also be determined whether it is destroyed by 9 inhibitors. Finally, motor activation can be measured in an open field chamber. For all suggested experiments, multiple doses of MMP-2 and / or MMP-9 inhibitors, saline controls, and positive controls (eg, varenicline or bupropion as a positive control to measure nicotine addiction) As well as a total of 15 rodents per group / condition.

Example 130. Assay for determination of MMP-2 inhibition MMP-2 inhibitor activity was determined by the Knight method using an assay buffer consisting of 50 mM Tris-HCl (pH 7.6), 200 mM NaCl, 5 mM CaCl ₂ , and 1 μM ZnSO ₄ ( Knight, CG et al., FEBS LETT. 296 (3), (1992), 263-266). The concentration of the MMP inhibitor of the present invention was tested in duplicate (1 micromolar). The catalytic domain of MMP-2 (human recombinant) enzyme (10 nanomolar) was added to the compound solution. The mixture of enzyme and compound in assay buffer was then mixed thoroughly and incubated at 37 ° C. for 60 minutes. Upon completion of the incubation, the assay was initiated by the addition of 10 μM fluorescent substrate Mca-PLGL-Dpa-A-R-NH2 (Kd ca. 8 micromolar). The fluorescent product McaPLG was then measured by an automated plate multireader at 37 ° C. with an excitation wavelength of 355 nm and an emission wavelength of 405 nm. Positive controls were individually measured using the broad spectrum MMP inhibitor GM6001 as a control compound (MMP-2 IC50 = 0.5 nanomolar). Table 7 summarizes the results of inhibition studies.

実施例１３１．ＭＭＰ−９阻害決定のためのアッセイ
ＭＭＰ−９インヒビター活性を、５０ｍＭ Ｔｒｉｓ−ＨＣｌ（ｐＨ７．６）、２００ｍＭ ＮａＣｌ、５ｍＭ ＣａＣｌ_２、および１μＭ ＺｎＳＯ_４から構成されるアッセイバッファーを使用したＢｉｃｋｅｔｔ、Ｄ．Ｍ．の方法（Ｂｉｃｋｅｔｔ，Ｄ．Ｍ．ら、Ａｎａｌｙｔｉｃａｌ Ｂｉｏｃｈｅｍｉｓｔｒｙ ２１２，（１９９３），５８−６４）によって行った。本発明のＭＭＰインヒビターの濃度を、二連で試験した（１マイクロモル濃度）。ＭＭＰ−９（ヒト組換え）酵素（１０ナノモル濃度）の触媒ドメインを、化合物溶液に添加した。次いで、酵素および化合物のアッセイバッファー中の混合物を完全に混合し、３７℃で６０分間インキュベートした。インキュベーション完了の際、アッセイを、１０μＭの蛍光基質ＤＮＰ−Ｐｒｏ−Ｃｈａ−Ｇｌｙ−Ｃｙｓ（Ｍｅ）−Ｈｉｓ−Ａｌａ−Ｌｙｓ（Ｎ−Ｍｅ−Ａｂｚ）−ＮＨ２［Ｃｈａ＝β−シクロヘキシルアラニル；Ａｂｚ＝２−アミノベンゾイル（アントラニロイル））（Ｋｄ約７マイクロモル濃度）の添加によって開始した。次いで、蛍光生成物ＤｎｐＰＣｈａＧを、自動プレートマルチリーダーによって３７℃にて励起波長３６５ｎｍおよび発光波長４５０ｎｍで測定した。ポジティブコントロールを、コントロール化合物として広域スペクトルＭＭＰインヒビターＧＭ６００１を使用して個別に測定した（ＭＭＰ−９ ＩＣ５０＝０．２ナノモル濃度）。表８に阻害研究の結果をまとめている。

Example 131. Assay for MMP-9 Inhibition Determination MMP-9 inhibitor activity was measured in Bickett, D. using an assay buffer composed of 50 mM Tris-HCl (pH 7.6), 200 mM NaCl, 5 mM CaCl ₂ , and 1 μM ZnSO ₄ . M.M. (Bickett, DM, et al., Analytical Biochemistry 212, (1993), 58-64). The concentration of the MMP inhibitor of the present invention was tested in duplicate (1 micromolar). The catalytic domain of MMP-9 (human recombinant) enzyme (10 nanomolar) was added to the compound solution. The mixture of enzyme and compound in assay buffer was then mixed thoroughly and incubated at 37 ° C. for 60 minutes. Upon completion of the incubation, the assay was performed with 10 μM fluorescent substrate DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (N-Me-Abz) -NH2 [Cha = β-cyclohexylalanyl; Abz = Started by the addition of 2-aminobenzoyl (anthraniloyl)) (Kd about 7 micromolar). The fluorescent product DnpPChaG was then measured by an automated plate multireader at 37 ° C. with an excitation wavelength of 365 nm and an emission wavelength of 450 nm. Positive controls were individually measured using the broad spectrum MMP inhibitor GM6001 as a control compound (MMP-9 IC50 = 0.2 nanomolar). Table 8 summarizes the results of inhibition studies.

実施例１３２．ＭＭＰ−１阻害決定のためのアッセイ
本発明のＭＭＰインヒビターのＭＭＰ−１インヒビター活性の測定に関心がある場合、５０ｍＭ Ｔｒｉｓ−ＨＣｌ（ｐＨ７．６）、２００ｍＭ ＮａＣｌ、５ｍＭ ＣａＣｌ_２、および１μＭ ＺｎＳＯ_４を含むアッセイバッファーを使用するＫｎｉｇｈｔの方法（Ｋｎｉｇｈｔ，Ｃ．Ｇ．ら，ＦＥＢＳ ＬＥＴＴ．２９６（３），（１９９２），２６３−２６６）を使用することができる。１つの濃度を二連で試験することができる（すなわち、１マイクロモル濃度）。次いで、ＭＭＰ−１（ヒト組換え）酵素の触媒ドメインを、化合物溶液に添加することができる。次いで、酵素および化合物のアッセイバッファー中の混合物を完全に混合し、３７℃で６０分間インキュベートする。インキュベーション完了の際、アッセイを、１０μＭの蛍光基質ＤＮＰ−Ｐｒｏ−Ｃｈａ−Ｇｌｙ−Ｃｙｓ（Ｍｅ）−Ｈｉｓ−Ａｌａ−Ｌｙｓ（Ｎ−Ｍｅ−Ａｂｚ）−ＮＨ２［Ｃｈａ＝β−シクロヘキシルアラニル；Ａｂｚ＝２−アミノベンゾイル（アントラニロイル）］（１０μＭ）の添加によって開始する。次いで、蛍光生成物ＤｎｐＰＣｈａＧを、自動プレートマルチリーダーによって３７℃にて励起波長３６５ｎｍおよび発光波長４５０ｎｍで測定することができる。ポジティブコントロールを、コントロール化合物として広域スペクトルＭＭＰインヒビターであるＴｙｒ−ヒドロキサム酸を使用して個別に測定することもできる。

Example 132. Assay for determining MMP-1 inhibition If you are interested in measuring the MMP-1 inhibitor activity of the MMP inhibitors of the present invention, add 50 mM Tris-HCl (pH 7.6), 200 mM NaCl, 5 mM CaCl ₂ , and 1 μM ZnSO ₄ . The Knight method (Knight, CG, et al., FEBS LETT. 296 (3), (1992), 263-266) using an assay buffer can be used. One concentration can be tested in duplicate (ie, 1 micromolar concentration). The catalytic domain of the MMP-1 (human recombinant) enzyme can then be added to the compound solution. The mixture of enzyme and compound in assay buffer is then mixed thoroughly and incubated at 37 ° C. for 60 minutes. Upon completion of the incubation, the assay was performed with 10 μM fluorescent substrate DNP-Pro-Cha-Gly-Cys (Me) -His-Ala-Lys (N-Me-Abz) -NH2 [Cha = β-cyclohexylalanyl; Abz = Start by the addition of 2-aminobenzoyl (anthraniloyl)] (10 μM). The fluorescent product DnpPChaG can then be measured by an automated plate multireader at 37 ° C. with an excitation wavelength of 365 nm and an emission wavelength of 450 nm. Positive controls can also be measured individually using Tyr-hydroxamic acid, a broad spectrum MMP inhibitor, as a control compound.

Example 133. Assay for determining MMP-7 inhibition If you are interested in measuring the MMP-7 inhibitor activity of the MMP inhibitors of the present invention, add 50 mM Tris-HCl (pH 7.6), 200 mM NaCl, 5 mM CaCl ₂ , and 1 μM ZnSO ₄ . The Knight method (Knight, CG, et al., FEBS LETT. 296 (3), (1992), 263-266) using an assay buffer can be used. One concentration can be tested in duplicate (ie, 1 micromolar concentration). The catalytic domain of the MMP-7 (human recombinant) enzyme can then be added to the compound solution. The mixture of enzyme and compound in assay buffer is then mixed thoroughly and incubated at 37 ° C. for 60 minutes. Upon completion of incubation, the assay is initiated by the addition of 10 μM of the fluorescent substrate Mca-PLGL-Dpa-A-R-NH2. The fluorescent product McaPLG can then be measured by an automated plate multireader at 37 ° C. with an excitation wavelength of 355 nm and an emission wavelength of 405 nm. Positive controls can also be measured individually using Tyr-hydroxamic acid, a broad spectrum MMP inhibitor, as a control compound.

Example 134. Assay for determination of MMP-3 inhibition If you are interested in measuring the MMP-3 inhibitor activity of the MMP inhibitors of the present invention, add 50 mM Tris-HCl (pH 7.6), 200 mM NaCl, 5 mM CaCl ₂ , and 1 μM ZnSO ₄ . The Knight method (Knight, CG, et al., FEBS LETT. 296 (3), (1992), 263-266) using an assay buffer can be used. One concentration can be tested in duplicate (ie, 1 micromolar concentration). The catalytic domain of the MMP-3 (human recombinant) enzyme can then be added to the compound solution. The mixture of enzyme and compound in assay buffer is then mixed thoroughly and incubated at 37 ° C. for 60 minutes. Upon completion of the incubation, the assay is initiated by the addition of 10 μM fluorescent substrate McaRPKPVENvalWRK (Dnp) NH ₂ . The fluorescent product McaRPK can then be measured by an automated plate multireader at 37 ° C. with an excitation wavelength of 355 nm and an emission wavelength of 405 nm. Positive controls can also be measured individually using Tyr-hydroxamic acid, a broad spectrum MMP inhibitor, as a control compound.

Example 135. Assays for determining MMP-12 inhibition MMP-12 inhibitor activity is determined by first separating cleaved and non-cleaved substrates by charge by electrophoretic mobility shift, followed by fluorescence measurement of the separated products, This can be done by determining inhibition of enzyme activity relative to a control reaction. An MMP-12 assay can then be performed using an assay buffer composed of 100 mM HEPES (pH 7.5), 0.01% Brij-35, 1.5 mM NaCl, and 2 mM CaCl ₂ . One inhibitor concentration can be tested in duplicate (ie, 1 micromolar). The reaction can be initiated by first adding the substrate and then incubating the reaction mixture for 1 hour at room temperature. The reaction can then be stopped by the addition of stop buffer consisting of 100 mM HEPES (pH 7.5), 30 mM EDTA, 0.015% Brij-35, and 5% DMSO. Positive controls can then be individually measured using GM6001, a broad spectrum MMP inhibitor, as a control compound.

Example 136. Assay for determining MMP-13 inhibition If you are interested in measuring the MMP-13 inhibitor activity of the MMP inhibitors of the present invention, include 50 mM Tris-HCl (pH 7.6), 200 mM NaCl, 5 mM CaCl ₂ , and 1 μM ZnSO 4. The Knight method using assay buffer (Knight, CG, et al., FEBS LETT. 296 (3), (1992), 263-266) can be used. One concentration can be tested in duplicate (ie, 1 micromolar concentration). The catalytic domain of the MMP-13 (human recombinant) enzyme can then be added to the compound solution. The mixture of enzyme and compound in assay buffer is then mixed thoroughly and incubated at 37 ° C. for 60 minutes. During incubation is complete, assay is initiated by the addition of the fluorogenic substrate Mca-P-L-G- L-Dpa-A-R-NH 2 in 10 [mu] M. The fluorescent product McaPLG can then be measured by an automated plate multireader at 37 ° C. with an excitation wavelength of 355 nm and an emission wavelength of 405 nm. Positive controls can also be measured individually using Tyr-hydroxamic acid, a broad spectrum MMP inhibitor, as a control compound.

（式中、
Ｒ ^１ 、Ｒ ^２ は、水素、ハロ、アルキル、シクロアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヒドロキシ、アルコキシ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、アルケニル、アルキニル、ＮＯ _２ 、ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ Ｎ＝ＣＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＳＯ _２ Ｒ ^９ 、ＣＮ、Ｃ（Ｏ）ＯＲ ^９ 、およびフルオロアルキルからなる群から独立して選択され、ここで、アルキル、シクロアルキル、アルコキシ、アルケニル、アルキニル、およびフルオロアルキルは１回以上任意選択的に置換され、ヘテロシクロアルキル縮合ヘテロアリールアルキルは１回以上任意選択的に置換される）からなる群から選択される化合物、そのＮ−オキシド、重水素化アナログ、薬学的に許容され得る塩、プロドラッグ、処方物、多形、互変異性体、ラセミ混合物、および立体異性体。
（項目２）
以下：

からなる群から選択される化合物、またはその薬学的に許容され得る塩もしくは重水素化アナログ。
（項目３）
有効量の項目１に記載の化合物および薬学的に許容され得るキャリアを含む薬学的組成物。
（項目４）
メタロプロテイナーゼ酵素を阻害する医薬として使用するための、以下：

（式中、
Ｒ ^１ 、Ｒ ^２ は、水素、ハロ、アルキル、シクロアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヒドロキシ、アルコキシ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、アルケニル、アルキニル、ＮＯ _２ 、ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ Ｎ＝ＣＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＳＯ _２ Ｒ ^９ 、ＣＮ、Ｃ（Ｏ）ＯＲ ^９ 、およびフルオロアルキルからなる群から独立して選択され、ここで、アルキル、シクロアルキル、アルコキシ、アルケニル、アルキニル、およびフルオロアルキルは１回以上任意選択的に置換され、ヘテロシクロアルキル縮合ヘテロアリールアルキルは１回以上任意選択的に置換される）からなる群から選択される化合物、そのＮ−オキシド、重水素化アナログ、薬学的に許容され得る塩、プロドラッグ、処方物、多形、互変異性体、ラセミ混合物、および立体異性体。
（項目５）
前記メタロプロテアーゼ酵素が、ＭＭＰ−１、ＭＭＰ−２、ＭＭＰ−３、ＭＭＰ−７、ＭＭＰ−９、ＭＭＰ−１２、およびＭＭＰ−１３からなる群から選択される１つ以上の酵素を含む、項目４に記載の使用。
（項目６）
前記メタロプロテアーゼ酵素が、ＭＭＰ−２、ＭＭＰ−９、またはその両方である、項目４に記載の使用。
（項目７）
前記メタロプロテアーゼ酵素がＭＭＰ−２酵素である、項目４に記載の使用。
（項目８）
ＭＭＰ媒介容態を処置するための医薬として使用するための、以下：

（式中、
Ｒ ^１ 、Ｒ ^２ は、水素、ハロ、アルキル、シクロアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヒドロキシ、アルコキシ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、アルケニル、アルキニル、ＮＯ _２ 、ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ Ｎ＝ＣＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＳＯ _２ Ｒ ^９ 、ＣＮ、Ｃ（Ｏ）ＯＲ ^９ 、およびフルオロアルキルからなる群から独立して選択され、ここで、アルキル、シクロアルキル、アルコキシ、アルケニル、アルキニル、およびフルオロアルキルは１回以上任意選択的に置換され、ヘテロシクロアルキル縮合ヘテロアリールアルキルは１回以上任意選択的に置換される）からなる群から選択される化合物、そのＮ−オキシド、重水素化アナログ、薬学的に許容され得る塩、プロドラッグ、処方物、多形、互変異性体、ラセミ混合物、および立体異性体。
（項目９）
前記容態が、疼痛に対する感受性の増強または悪化；急性疼痛；熱傷痛；非定型顔面痛；神経因性疼痛；背部痛；複合性局所疼痛症候群Ｉ型およびＩＩ型；関節痛；スポーツ損傷痛；ウイルス感染に関連する疼痛；幻肢痛；分娩陣痛；癌性疼痛；化学療法後疼痛；卒中後疼痛；術後疼痛；生理学的疼痛；炎症性疼痛；急性炎症状態；内臓痛；神経痛；有痛性糖尿病性ニューロパシー；外傷性神経損傷；脊髄損傷；麻痺；加齢；再灌流障害；外傷；組織に対する化学物質曝露または酸化的損傷；創傷治癒；皮膚の美化；嗜癖、ならびに／または嗜癖物質からの耐性および離脱からなる群から選択される、項目８に記載の使用。
（項目１０）
前記疼痛に対する感受性の増強または悪化が、痛覚過敏、カウザルギー、および異痛症からなる群から選択される、項目９に記載の使用。
（項目１１）
前記ウイルス感染に関連する疼痛が、ＨＩＶ痛、ポストポリオ症候群、および疱疹後神経痛からなる群から選択される、項目９に記載の使用。
（項目１２）
前記内臓痛が、アンギナ、過敏性腸症候群（ＩＢＳ）、および炎症性腸疾患からなる群から選択される、項目９に記載の使用。
（項目１３）
ＭＭＰ媒介疾患を処置するための医薬として使用するための、以下：

（式中、
Ｒ ^１ 、Ｒ ^２ は、水素、ハロ、アルキル、シクロアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヒドロキシ、アルコキシ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、アルケニル、アルキニル、ＮＯ _２ 、ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ Ｎ＝ＣＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＳＯ _２ Ｒ ^９ 、ＣＮ、Ｃ（Ｏ）ＯＲ ^９ 、およびフルオロアルキルからなる群から独立して選択され、ここで、アルキル、シクロアルキル、アルコキシ、アルケニル、アルキニル、およびフルオロアルキルは１回以上任意選択的に置換され、ヘテロシクロアルキル縮合ヘテロアリールアルキルは１回以上任意選択的に置換される）からなる群から選択される化合物、そのＮ−オキシド、重水素化アナログ、薬学的に許容され得る塩、プロドラッグ、処方物、多形、互変異性体、ラセミ混合物、および立体異性体。
（項目１４）
前記疾患が、関節リウマチ、変形性関節症、腹部大動脈瘤、癌、炎症、アテローム性動脈硬化症、多発性硬化症、慢性閉塞性肺疾患、眼疾患、神経疾患、精神疾患、血栓症、細菌感染、パーキンソン病、疲労、震え、糖尿病性網膜症、網膜の血管疾患、認知症、心筋症、腎尿細管障害、糖尿病、精神病、ジスキネジア、色素異常、聴覚消失、炎症線維症候群、腸症候群、アレルギー、アルツハイマー病、動脈プラーク形成、歯周疾患、ウイルス感染、アルコール依存症（ａｌｃｈｏｌｉｓｍ）、薬物乱用、卒中、アテローム性動脈硬化症、心血管疾患、痔核、および疼痛を生じる疾患からなる群から選択される、項目１３に記載の使用。
（項目１５）
前記容態が神経因性疼痛である、項目９に記載の使用。
（項目１６）
前記容態が変形性関節症痛である、項目９に記載の使用。
（項目１７）
前記容態が炎症性疼痛である、項目９に記載の使用。
（項目１８）
前記容態が物質嗜癖である、項目９に記載の使用。
（項目１９）
前記嗜癖物質が、オピオイド、アンフェタミン、コカイン、モルヒネ、アルコール、タバコ、ニコチン、および大麻からなる群から選択される、項目１８に記載の容態。
（項目２０）
Ａ）有効量の以下：

（式中、
Ｒ ^１ 、Ｒ ^２ は、水素、ハロ、アルキル、シクロアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル縮合ヘテロアリールアルキル、ヘテロシクロアルキル、ビシクロアルキル、ヘテロビシクロアルキル、スピロアルキル、スピロヘテロアルキル、アリール、ヘテロアリール、シクロアルキル縮合アリール、ヘテロシクロアルキル縮合アリール、シクロアルキル縮合ヘテロアリール、ヘテロシクロアルキル縮合ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、ビシクロアルキルアルキル、ヘテロビシクロアルキルアルキル、スピロアルキルアルキル、スピロヘテロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、シクロアルキル縮合アリールアルキル、ヘテロシクロアルキル縮合アリールアルキル、シクロアルキル縮合ヘテロアリールアルキル、ヒドロキシ、アルコキシ、アリール、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、アルケニル、アルキニル、ＮＯ _２ 、ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＮＲ ^９ Ｒ ^９ 、ＮＲ ^９ Ｎ＝ＣＲ ^９ Ｒ ^９ 、ＮＲ ^９ ＳＯ _２ Ｒ ^９ 、ＣＮ、Ｃ（Ｏ）ＯＲ ^９ 、およびフルオロアルキルからなる群から独立して選択され、ここで、アルキル、シクロアルキル、アルコキシ、アルケニル、アルキニル、およびフルオロアルキルは１回以上任意選択的に置換され、ヘテロシクロアルキル縮合ヘテロアリールアルキルは１回以上任意選択的に置換される）からなる群から選択される化合物、そのＮ−オキシド、重水素化アナログ、薬学的に許容され得る塩、プロドラッグ、処方物、多形、互変異性体、ラセミ混合物、および立体異性体、
Ｂ）薬学的に許容され得るキャリア、および
Ｃ）（ａ）疾患修飾性抗リウマチ薬；（ｂ）非ステロイド性抗炎症薬；（ｃ）ＣＯＸ−２選択的インヒビター；（ｄ）ＣＯＸ−１インヒビター；（ｅ）免疫抑制薬；（ｆ）ステロイド；（ｇ）生物学的応答調節物質；（ｈ）オピオイド；および（ｉ）炎症誘発性サイトカイン産生の低分子インヒビターからなる群から選択されるメンバー
を含む薬学的組成物。
（項目２１）
有効量の少なくとも１つの項目２に記載の化合物および薬学的に許容され得るキャリアを含む薬学的組成物。 The MMP-2 inhibitory compound and / or MMP-9 inhibitory compound of the present invention may be used as a disease-modifying antirheumatic drug, non-steroidal anti-inflammatory drug, COX-2 selective inhibitor, COX-1 inhibitor, immunosuppressive drug, steroid, It can be used in combination with biological response modifiers or other anti-inflammatory agents.
In one embodiment, for example, the following items are provided.
(Item 1)
Less than:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer.
(Item 2)
Less than:

A compound selected from the group consisting of: or a pharmaceutically acceptable salt or deuterated analog thereof.
(Item 3)
A pharmaceutical composition comprising an effective amount of the compound of item 1 and a pharmaceutically acceptable carrier.
(Item 4)
For use as a medicament that inhibits a metalloproteinase enzyme, the following:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer.
(Item 5)
Item wherein the metalloprotease enzyme comprises one or more enzymes selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13. 4. Use according to 4.
(Item 6)
Item 5. The use according to Item 4, wherein the metalloprotease enzyme is MMP-2, MMP-9, or both.
(Item 7)
Item 5. Use according to item 4, wherein the metalloprotease enzyme is an MMP-2 enzyme.
(Item 8)
For use as a medicament for treating an MMP-mediated condition, the following:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer.
(Item 9)
The condition is increased or worsened sensitivity to pain; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex local pain syndrome types I and II; joint pain; Pain associated with viral infection; Phantom limb pain; Labor labor; Cancer pain; Post-chemotherapy pain; Post-stroke pain; Postoperative pain; Physiological pain; Inflammatory pain; Acute inflammatory condition; Diabetic neuropathy; traumatic nerve injury; spinal cord injury; paralysis; aging; reperfusion injury; trauma; chemical exposure to tissues or oxidative damage; wound healing; skin beautification; addiction and / or from addiction substances 9. Use according to item 8, selected from the group consisting of tolerance and withdrawal.
(Item 10)
10. Use according to item 9, wherein the increased or worsened sensitivity to pain is selected from the group consisting of hyperalgesia, causalgia, and allodynia.
(Item 11)
10. Use according to item 9, wherein the pain associated with the viral infection is selected from the group consisting of HIV pain, post-polio syndrome, and postherpetic neuralgia.
(Item 12)
10. Use according to item 9, wherein the visceral pain is selected from the group consisting of angina, irritable bowel syndrome (IBS), and inflammatory bowel disease.
(Item 13)
For use as a medicament for treating MMP mediated diseases, the following:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer.
(Item 14)
The disease is rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, eye disease, neurological disease, psychiatric disease, thrombosis, bacteria Infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, retinal vascular disease, dementia, cardiomyopathy, renal tubule disorder, diabetes, psychosis, dyskinesia, pigmentation abnormality, hearing loss, inflammatory fiber syndrome, bowel syndrome, allergy Selected from the group consisting of: Alzheimer's disease, arterial plaque formation, periodontal disease, viral infection, alcoholism, drug abuse, stroke, atherosclerosis, cardiovascular disease, hemorrhoids, and pain-causing diseases Use according to Item 13.
(Item 15)
10. Use according to item 9, wherein the condition is neuropathic pain.
(Item 16)
Item 10. The use according to Item 9, wherein the condition is osteoarthritis pain.
(Item 17)
10. Use according to item 9, wherein the condition is inflammatory pain.
(Item 18)
Item 10. Use according to Item 9, wherein the condition is substance addiction.
(Item 19)
Item 19. The condition according to Item 18, wherein the addictive substance is selected from the group consisting of opioids, amphetamines, cocaine, morphine, alcohol, tobacco, nicotine, and cannabis.
(Item 20)
A) Effective amount of:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex forms, racemic mixtures, and stereoisomers,
B) a pharmaceutically acceptable carrier, and
C) (a) disease modifying anti-rheumatic drugs; (b) non-steroidal anti-inflammatory drugs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs; (f) A member selected from the group consisting of: a steroid; (g) a biological response modifier; (h) an opioid; and (i) a small molecule inhibitor of pro-inflammatory cytokine production.
A pharmaceutical composition comprising:
(Item 21)
A pharmaceutical composition comprising an effective amount of at least one compound of item 2 and a pharmaceutically acceptable carrier.

Claims (21)

Less than:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer. Less than:

A compound selected from the group consisting of: or a pharmaceutically acceptable salt or deuterated analog thereof. A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. For use as a medicament that inhibits a metalloproteinase enzyme, the following:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer. The metalloprotease enzyme comprises one or more enzymes selected from the group consisting of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13. Item 4. Use according to Item 4. Use according to claim 4, wherein the metalloprotease enzyme is MMP-2, MMP-9, or both. Use according to claim 4, wherein the metalloprotease enzyme is an MMP-2 enzyme. For use as a medicament for treating an MMP-mediated condition, the following:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer. The condition is increased or worsened sensitivity to pain; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex local pain syndrome types I and II; joint pain; Pain associated with viral infection; Phantom limb pain; Labor labor; Cancer pain; Post-chemotherapy pain; Post-stroke pain; Postoperative pain; Physiological pain; Inflammatory pain; Acute inflammatory condition; Diabetic neuropathy; traumatic nerve injury; spinal cord injury; paralysis; aging; reperfusion injury; trauma; chemical exposure to tissues or oxidative damage; wound healing; skin beautification; addiction and / or from addiction substances 9. Use according to claim 8, selected from the group consisting of tolerance and withdrawal. 10. Use according to claim 9, wherein the increased or worsened sensitivity to pain is selected from the group consisting of hyperalgesia, causalgia, and allodynia. The use according to claim 9, wherein the pain associated with the viral infection is selected from the group consisting of HIV pain, post-polio syndrome, and postherpetic neuralgia. 10. Use according to claim 9, wherein the visceral pain is selected from the group consisting of angina, irritable bowel syndrome (IBS), and inflammatory bowel disease. For use as a medicament for treating MMP mediated diseases, the following:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex, racemic mixture, and stereoisomer. The disease is rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer, inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, eye disease, neurological disease, psychiatric disease, thrombosis, bacteria Infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, retinal vascular disease, dementia, cardiomyopathy, renal tubule disorder, diabetes, psychosis, dyskinesia, pigmentation abnormality, hearing loss, inflammatory fiber syndrome, bowel syndrome, allergy Selected from the group consisting of: Alzheimer's disease, arterial plaque formation, periodontal disease, viral infection, alcoholism, drug abuse, stroke, atherosclerosis, cardiovascular disease, hemorrhoids, and pain-causing diseases The use according to claim 13. Use according to claim 9, wherein the condition is neuropathic pain. Use according to claim 9, wherein the condition is osteoarthritic pain. Use according to claim 9, wherein the condition is inflammatory pain. Use according to claim 9, wherein the condition is substance addiction. 19. The condition of claim 18, wherein the addictive substance is selected from the group consisting of opioids, amphetamines, cocaine, morphine, alcohol, tobacco, nicotine, and cannabis. A) Effective amount of:

(Where
R ¹ and R ² are hydrogen, halo, alkyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, Cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused Arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl Heteroarylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused hetero Aryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cyclo Alkyl-fused heteroarylalkyl, hydroxy, alkoxy, aryl, heteroary , Arylalkyl, heteroarylalkyl, alkenyl, _{^{alkynyl, NO 2, NR 9 R 9}} , NR 9 NR 9 R 9, NR 9 N = CR 9 R 9, NR 9 SO 2 R 9, CN, C (O) OR ⁹ and independently selected from the group consisting of fluoroalkyl, wherein alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, and fluoroalkyl are optionally substituted one or more times, and heterocycloalkyl fused heteroarylalkyl Is optionally substituted one or more times), N-oxides, deuterated analogs, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers Sex forms, racemic mixtures, and stereoisomers,
B) a pharmaceutically acceptable carrier, and C) (a) a disease modifying anti-rheumatic drug; (b) a non-steroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor A member selected from the group consisting of: (e) an immunosuppressant; (f) a steroid; (g) a biological response modifier; (h) an opioid; and (i) a small molecule inhibitor of proinflammatory cytokine production. A pharmaceutical composition comprising. A pharmaceutical composition comprising an effective amount of at least one compound of claim 2 and a pharmaceutically acceptable carrier.

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